Medication system

ABSTRACT

A method for delivering therapeutics includes infusing medication with cannabis.

FIELD OF THE INVENTION

This invention relates to medical dispensers.

BACKGROUND OF THE INVENTION

Cannabis is a substance derived from the hemp plant (Cannabis indica orCannabis sativa); the leaves and stalks of these plants may be referredto as hashish or marijuana. The term cannabis may refer to the femaleflowering heads of hemp, or to a resin obtained from the flowering headsthat may also be referred to as cannabin. Derived materials includecannaboid, an alkaloid cannabine, and an oil cannabinol. In thisspecification these, and other derivatives, are referred to genericallyas cannabis.

SUMMARY

A delivery system is disclosed. The delivery system includes transdermalpatches, aerosol sprays, or injectable needles/cannulas. In oneembodiment, the injectable needles/cannulas are 3D printed hyaluronicacid structures that are hard structures prior to use and when in use,the hyaluronic acid expands upon contact with liquid and create adelivery pathway.

In a second aspect, the transdermal patches have a plurality of needlesmade from hyaluronic acid (HA). In a first state, the HA is a solid thatcan penetrate the skin. In a second state, with liquid, the HA becomesexpanded to release drug/medication into the skin penetration to deliverdrug or solution.

In another aspect, a slow release system using HA and a drug isdisclosed. The HA is cross-linked to provide predetermined dissolutionto release the medication in different layers of HA for release overtime.

In another aspect, CBD can be delivered by mixing blended cannabismaterial with hyaluronic acid (HA); identifying cancerous cells in abody; and contacting the HA infused with cannabis into the body portionwith cancerous cells.

In another aspect, CBD can be delivered by encapsulating cannabismaterial with hyaluronic acid (HA); cross-linking the HA to provide aslow release cannabis; identifying cancerous cells in a body; andcontacting the HA infused with cannabis into the body portion withcancerous cells for time release. Cannabinoid are hydrophobic while HAis hydrophilic so the HA can bind to body better than cannabis alone sothat the cannabis can treat the area.

In another aspect, cannabis can be extracted and infused with oil andsuch infused cannabis can be used in one of: candy, baked good, popcorn,gummies, shampoo, conditioner, lotions, soaps, massage oils, lip balm,salad dressings, mayonnaise, margarine, sugar free food. The oil infusedcannabis can also be used in one of: cosmetic good, medication, aerosolspray.

Advantages of the preferred embodiments may include one or more of thefollowing. The process provides for efficient delivery of cannabis at alow cost. The resulting oil with cannabis is usable immediately and theeffects are long lasting and near instant. The Oil is a healthyalternative to butter and all types of other oils, which allows vegansto enjoy cannabis. It can be eaten directly or put into many products.The cannabis can be delivered as a spray, dermal patch, slow releasedrug or as food such as hard candies, baked goods (brownies, cookies),popcorn, gummies, shampoo, conditioner, lotions, soaps, massage oils,lip balm, salad dressings, mayonnaise, and margarine. The oil can alsobe used for cosmetics and drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be further and more particularly described, byway of example only, and with reference to the accompanying drawings inwhich:

FIGS. 1-2 show an exemplary transdermal patch.

FIG. 3 shows a diagrammatic view of an apparatus for spraying a cannabisaerosol.

FIG. 4 shows an exemplary e-cigarette for inhaling vapors of cannabis.

DESCRIPTION

A delivery system is disclosed. The delivery system includes transdermalpatches, aerosol sprays, or injectable needles/cannulas. The deliverysystem can handle water insoluble drugs like cannabinoids/cannabiol(CBD). Cannabinoids are a group of 21-carbon-containing terpenophenoliccompounds produced uniquely by Cannabis species (e.g., Cannabis sativaL.), referred to as phytocannabinoids. Althoughdelta-9-tetrahydrocannabinol (THC) is the primary psychoactiveingredient, other known compounds with biologic activity are cannabinol,cannabidiol (CBD), cannabichromene, cannabigerol,tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thoughtto have significant analgesic and anti-inflammatory activity without thepsychoactive effect (high) of delta-9-THC. Cannabinoids are effective inpain relief and curing certain types of cancer. Since cannabinoids arenot easily water soluble there is a delayed in absorbance and the effectfelt in patients for a slow release in the case of pain relief patches.The patches are compose of several thin layers assembled together andusually release one of several opioids through the skin for about 72hours. In one embodiment, the injectable needles/cannulas are 3D printedhyaluronic acid structures that are hard structures prior to use andwhen in use, the hyaluronic acid expands upon contact with liquid andcreate a delivery pathway.

FIGS. 1-2 show an exemplary transdermal patch 100 that provides efficacybenefits and can maintain a steady level of medication for a number ofdays. One exemplary patch uses slow release medication embedded inhyaluronic acid (HA) with hydrophobic molecules that can permeatethrough the lipid pathway. The physiological factors that affect drugabsorption include skin age, gender, ethnicity, the thickness of thestratum corneum (which varies between different anatomical sites), thedegree of skin hydration, the presence of hair follicles, skin condition(e.g., disease compromises the natural barrier function of the skin),temperature, and metabolism. In terms of physicochemical factors,properties such as drug solubility, partition coefficient, molecularmass, and whether the drug is in an ionized or unionized form willinfluence transdermal absorption.

The transdermal patch 100 that contains a drug delivery assembly 170 anda microneedle assembly 180 containing a plurality of needles made fromhyaluronic acid (HA). In a first state, the HA is a solid that canpenetrate the skin. In a second state, with liquid, the HA becomesexpanded to release drug/medication into the skin penetration to deliverdrug or solution. The drug delivery assembly 170 includes a reservoir106 positioned adjacent to a rate control membrane 108, such asdescribed above. Although optional, the assembly 170 also contains anadhesive layer 104 that is positioned adjacent to the reservoir 106. Themicroneedle assembly 180 likewise includes a support 112 from whichextends a plurality of microneedles 130 having channels 131, such asdescribed above. The layers of the drug delivery assembly 170 and/or themicroneedle assembly 180 may be attached together if desired using anyknown bonding technique, such as through adhesive bonding, thermalbonding, ultrasonic bonding, etc.

Regardless of the particular configuration employed, the patch 100 alsocontains a release member 110 that is positioned between the drugdelivery assembly 170 and the microneedle assembly 180. While therelease member 110 may optionally be bonded to the adjacent support 112and/or rate control membrane 108, it is typically desired that it isonly lightly bonded, if at all, so that the release member 110 can beeasily withdrawn from the patch 100. If desired, the release member 110may also contain a tab portion 171 that extends at least partly beyondthe perimeter of the patch 100 to facilitate the ability of a user tograb onto the member and pull it in the desired direction. In its“inactive” configuration as shown in FIGS. 1-2, the drug deliveryassembly 170 of the patch 100 securely retains a drug compound 107 sothat it does not flow to any significant extent into the microneedles130. As indicated above, the patch can be “activated” by simply applyinga force to the release member so that it is detached from the patch. Thedetachment of the release member immediately initiates the flow of thedrug compound to the microneedles because the drug delivery assembly isalready disposed in fluid communication with the microneedle assembly.In certain embodiments, the microneedle assembly is not initially influid communication with the drug delivery assembly. When it is desiredto use the patch, the user may physically manipulate the two separateassemblies into fluid communication. The release member may be separatedeither before or after such physical manipulation occurs. The hyaluronicacid microneedle structures that are hard structures prior to use andwhen in use, the hyaluronic acid expands upon contact with skin pores orbody liquid and create a delivery pathway.

The patch is ideal for the management of perioperative pain and chronicpain in patients suffering from conditions like diabetes and cancer.Another application is during vaccination for babies. The patch can beapplied on the baby's arm five minutes before the jab, for thepainkiller to set in. In this way, vaccination can potentially bepainless for babies. The patch can also deliver collagen for cosmeticand skincare purposes and for artificial skin replacement after a burnor accident, for example. The collagen can be encapsulated in themicroneedles and delivered up to the dermis layer of the skin, whilecurrent skincare products can only deliver to the outermost layer ofskin. The patch can also deliver botox through the large pores from theHA microneedles.

The number of microneedles shown in the figures is for illustrativepurposes only. The actual number of microneedles used in the patch may,for example, range from about 500 to about 10,000, in some embodimentsfrom about 2,000 to about 8,000, and in some embodiments, from about4,000 to about 6,000. The size and shape of the microneedles may alsovary as desired. For example, the microneedles have an overall conicalshape. In alternative embodiments, however, the microneedles 318 mayhave an overall pyramidal shape or a cylindrical portion upon which ispositioned a conical portion having a tip. The tip typically has aradius that is less than or equal to about 1 micrometer. Themicroneedles are typically of a length sufficient to penetrate thestratum corneum and pass into the epidermis, but not penetrate throughthe epidermis and into the dermis in applications where it is desirableto minimize pain. In certain embodiments, the microneedles have a length(from their tip to their base) of about 500 micrometers or less, in someembodiments from 1 to about 400 micrometers, and in some embodiments,from about 50 to about 350 micrometers.

The drug delivery assembly of the transdermal patch contains a reservoirthat can initially retain a drug compound. The term “reservoir”generally refers to a designated area or chamber configured to retain afluidic drug compound. The reservoir may be an open volume space, gel,solid structure, etc. Nevertheless, in most embodiments, the reservoiris a solid matrix through which the drug compound is capable of flowing.The selection of the desired materials for the matrix typically dependson the solubility and diffusivity of the target drug compound and thetime during which release is sought. In one embodiment, for example, thesolid matrix is generally impermeable to the compound, and the materialused to form the matrix is selected so that the drug compound is able todiffuse therethrough. In other embodiments, however, the solid matrixmay be permeable or semi-permeable to the drug compound so that it cansimply flow through its pores. Examples of such solid matrices includeporous fiber webs (e.g., woven or nonwoven), apertured films, foams,sponges, etc. Regardless of its particular form, polymeric materials areoften used to form the solid matrix, such as silicones, acrylic resins,acetate copolymers (e.g., ethylene vinyl acetate), plasticized polyvinylacetate/polyvinyl chloride resins, plasticized hydrolyzed polyvinylalcohol, rubber-based adhesives (e.g., polyisobutylenes extended with asolvent such as mineral oil), plasticized polyvinyl chloride,polyethylene glycols and polypropylene glycols of varying molecularweights, cellulose esters, polyolefins; etc.

There is no particular limitation to the drug compounds that may beretained within the reservoir and employed in the patch of the presentinvention. Suitable compounds may include, for instance, proteinaceouscompounds, such as insulin, immunoglobulins (e.g., IgG, IgM, IgA, IgE),TNF-α, antiviral medications, etc.; polynucleotide agents, such asplasmids, siRNA, RNAi, nucleoside anticancer drugs, vaccines, etc.;small molecule agents, such as alkaloids, glycosides, phenols, etc.;anti-infection agents, hormones, drugs regulating cardiac action orblood flow, pain control; and so forth. A non-limiting listing of agentsincludes anti-Angiogenesis agents, anti-depressants, antidiabeticagents, antihistamines, anti-inflammatory agents, butorphanol,calcitonin and analogs, COX-II inhibitors, dermatological agents,dopamine agonists and antagonists, enkephalins and other opioidpeptides, epidermal growth factors, erythropoietin and analogs, folliclestimulating hormone, glucagon, growth hormone and analogs (includinggrowth hormone releasing hormone), growth hormone antagonists, heparin,hirudin and hirudin analogs such as hirulog, IgE suppressors and otherprotein inhibitors, immunosuppressives, insulin, insulinotropin andanalogs, interferons, interleukins, leutenizing hormone, leutenizinghormone releasing hormone and analogs, monoclonal or polyclonalantibodies, motion sickness preparations, muscle relaxants, narcoticanalgesics, nicotine, non-steroid anti-inflammatory agents,oligosaccharides, parathyroid hormone and analogs, parathyroid hormoneantagonists, prostaglandin antagonists, prostaglandins, scopolamine,sedatives, serotonin agonists and antagonists, sexual hypofunction,tissue plasminogen activators, tranquilizers, vaccines with or withoutcarriers/adjuvants, vasodilators, major diagnostics such as tuberculinand other hypersensitivity agents. Vaccine formulations may include anantigen or antigenic composition capable of eliciting an immune responseagainst a human pathogen or from other viral pathogens.

Due to its controlled capillary flow, the patch can deliver highmolecular weight drug compounds such as botox. The term “high molecularweight” generally refers to compounds having a molecular weight of about1 kiliDalton (“kDa”) or more, in some embodiments about 10 kDa or more,in some embodiments about 20 kDa to about 250 kDa, and in someembodiments, from about greater than about 40 kDa to about 150 kDa.Examples of such high molecular weight compounds include proteintherapeutics, which refers to any biologically active proteinaceouscompound including, without limitation, natural, synthetic, andrecombinant compounds, fusion proteins, chimeras, and so forth, as wellas compounds including the 20 standard amino acids and/or syntheticamino acids. In one particular embodiment, the patch may be utilized intreatment of a chronic condition, such as rheumatoid arthritis (“RA”),to deliver a steady flow a drug to a subject in need thereof. RA drugcompounds may include symptom suppression compounds, such as analgesicsand anti-inflammatory drugs including both steroidal and non-steroidalanti-inflammatory drugs (NSAID), as well as disease-modifyingantirheumatic drugs (“DMARD”). The patch can include and deliver symptomsuppression compounds, such as analgesics and anti-inflammatory drugs,as well as DMARD compounds, including biological DMARDs. Throughutilization of the transdermal patch of the present invention, RA drugscan be delivered at a steady concentration over a sustained period. Thepatch can prevent the initial burst of concentration common whenutilizing previously known methods for delivery of RA drugs, includingoral delivery and injection.

One embodiment uses microneedles between 20 um to 1000 um in length,capable of puncturing the outermost layer of the epidermis (stratumcorneum) to create openings, or pores, relative to the size of theactive pharmaceutical agent being administered, in this situation thisbeing the cannabis agent, in which the ingredients can be delivered.This allows for the increase of permeability and decrease skin sensationwhen an agent is administered. However, there has been research onincreased permeation of mostly water-soluble compounds throughmicroneedle-treated aqueous pores, rather than an oil based agent suchas cannabidiols.

An embodiment example shown here comprises a pharmaceutical compositioncomprising a cannaboid, or cannabinoid prodrug incorporated into ahydrogel which is used in conjunction with a microneedle array for thetreatment of the targeted disease or condition that is responsive to acannabiod. Another possible embodiment consists of a microneedle arrayin which the pharmaceutical composition consists of a cannabidiolprodrug that consists of a COX inhibitor and/or a penetration enhancer.

Used here, “cannabinoid” includes any compound that interacts with acannabinoid receptor and various cannabinoid mimetics such as certaintetrahydropyran analogs. However, dues to its highly lipophilic nature,cannabidiol is poorly absorbed through membranes such as the skin ofmammals, including humans. Because of this, successfully trandermallyadministering effective quantities of cannabidiol to a mammal needs areasonable amount of time and certain amount of surface area.

In one embodiment, the composition to be put in the microneedle willcomprise a cannaboid, such as cannabidiol or the cannabidiol prodrug, ina total amount weight of the composition of about 0.1% to about 95%.Microneedles can be solid or hollow and are made from manybio-compatible materials, including silicon, biodegradable polymers, andstainless steel. Solid microneedles can be used to create channels ofpores in the skin, followed by an application of a transdermal patch tothe skin surface. Alternatively, solid microneedles can be first coatedwith an active pharmaceutical agent and then inserted into the skin.Hollow microneedles can also be used to facilitate active permeationthrough the pore in the microneedle and into the skin. Many studies haveshown that solid microneedles can increase skin permeability by up tofour orders of magnitude of compounds ranging in size from smallmolecules to proteins to nanoparticles. This is good news because thesize of the cannabidiols will be able to be used with the microneedleand be administered into the skin. The terminology “pharmaceuticalcomposition” used here includes any ointment, cream, solution,suspension, lotion, paste, gel, hydrogel, spray, foam, solid or oilwhich may be created or forms and used to administer a cannabinoid orcannabinoid prodrug. One embodiment may contain a penetration enhancingagent or co-solvent for transdermal to topical delivery. A penetrationenhancer is an excipient that aids in the diffusion of active componentthrough the stratum corneum of the skin. Many penetration enhancers alsofunction as co-solvents, which are thought to increase the solubility ofthe cannaboid in the composition and enhance drug delivery through themicroneedle-created pores in the skin. Appropriate enhancers to be usedshould be; highly potent (with a specific mechanism of action),demonstrate a rapid onset upon administration, have a predictableduration of action, have only non-permanent or reversible effects on theskin, be chemically stable, (vi) have no or minimal pharmacologicaleffects; (vii) be physically and chemically compatible with othercompositions, (viii) be odorless; (ix) be colorless; (x) behypoallergenic; (xi) be non-irritating; (xii) be non-phototoxic; (xii)be non-comedogenic; (xiv) have the solubility parameter approximatingthat of the skin (10.5 cal/cm3); (xv) be readily available; (xvi) beinexpensive; and (xvii) be able to be formulated in compositions fortopical or transdermal delivert of an active pharmaceutical agent.

Other drugs can be in the patch. For example, RA drugs that may beincorporated in the patch can include, without limitation, one or moreanalgesics, anti-inflammatories, DMARDs, herbal-based drugs, andcombinations thereof. Specific compounds can, of course, fall under oneor more of the general categories described herein. For instance, manycompounds function as both an analgesic and an anti-inflammatory;herbal-based drugs can likewise function as a DMARD as well as ananti-inflammatory. Moreover, multiple compounds that can fall under asingle category can be incorporated in the patch. For instance, thepatch can include multiple analgesics, such as acetaminophen withcodeine, acetaminophen with hydrocodone (vicodin), and so forth.Examples of analgesics and/or NSAIDs include analgesics available overthe counter (OTC) at relatively low dosages including acetamide(acetaminophen or paracetamol), acetylsalicylic acid (aspirin),ibuprofen, ketoprofen, naproxen and naproxen sodium, and so forth.Prescription analgesics and/or anti-inflammatories can include, withoutlimitation, OTC analgesics at concentrations requiring a prescription,celecoxib, sulindac, oxaprozin, salsalate, piroxicam, indomethacin,etodolac, meloxicam, nabumetone, keteroloc and ketorolac tromethamine,tolmetin, diclofenac, diproqualone, and diflunisal. Narcotic analgesicscan include codeine, hydrocodone, oxycodone, fentanyl, and propoxyphene.

DMARDs can encompass both small molecule drugs and biological agents.DMARDs may be chemically synthesized or may be produced through geneticengineering processes (e.g., recombinant techniques). Chemicallysynthesized DMARDs encompassed herein include, without limitation,azathioprine, cyclosporine (ciclosporin, cyclosporine A),D-penicillamine, gold salts (e.g., auranofin, Na-aurothiomalate(Myocrism), chloroquine, hydroxychloroquine, leflunomide, methotrexate,minocycline, sulphasalazine (sulfasalazine), and cyclophosphamide.Biological DMARDs include, without limitation, TNF-α blockers such asetanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®),certolizamab pego (Cimzia®) and golumumab (Simponi™); IL-1 blockers suchas anakinra (Kineret®); monoclonal antibodies against B cells includingrituximab (Rituxan®); T cell costimulation blockers such as abatacept(Orencia®), and IL-6 blockers such as tocilizumab (RoActemra®,Actemra®); a calcineurin inhibitor such as tacrolimus (Prograf®). Thepatch may also incorporate multiple RA drugs. For instance, the patchcan include a combination of DMARDs in addition to an analgesic and/oran anti-inflammatory drug. Common combinations of DMARDs include, forexample, methotrexate in combination with hydroxychloroquine,methotrexate in combination with sulfasalazine, sulfasalazine incombination with hydroxychloroquine, and all three of these DMARDstogether, i.e., hydroxychloroquine, methotrexate, and sulfasalazine.

If desired, the patch may employ a plurality of reservoirs for storingmultiple materials for delivery. The reservoirs may be positionedadjacent to each other, either in a vertical or horizontal relationship.For instance, a first reservoir may contain a drug compound and a secondreservoir may contain an excipient (e.g., delivery vehicle, such asalcohols, water, etc.; buffering agents; and so forth). In oneparticular embodiment, for example, the first reservoir may contain alyophilized powder of the drug compound (e.g., RA drug) and the secondreservoir may contain an aqueous solution for reconstituting the powder.Alternatively, multiple reservoirs may be employed that each contains adrug compound. Regardless, the different materials may be mixed prior todelivery.

The drug delivery assembly also contains a rate control membrane that isin fluid communication with the drug reservoir. The rate controlmembrane can help slow down the flow rate of the drug compound upon itsrelease. Specifically, fluidic drug compounds passing from the drugreservoir to the microneedle assembly may experience a drop in pressurethat results in a reduction in flow rate. If this difference is toogreat, some backpressure may be created that can impede the flow of thecompound and potentially overcome the capillary pressure of the fluidthrough the microfluidic channels. Thus, the use of the rate controlmembrane can ameliorate this difference in pressure and allow the drugcompound to be introduced into the microneedle at a more controlled flowrate. The particular materials, thickness, etc. of the rate controlmembrane can vary based on multiple factors, such as the viscosity ofthe drug compound, the desired delivery time, etc.

The rate-controlling membrane may be fabricated from permeable,semi-permeable or microporous materials that are known in the art tocontrol the rate of drug compounds and having a permeability to thepermeation enhancer lower than that of drug reservoir. For example, thematerial used to form the rate control membrane may have an average poresize of from about 50 nanometers to about 5 micrometers, in someembodiments from about 100 nanometers to about 2 micrometers, and insome embodiments, from about 300 nanometers to about 1 micrometer (e.g.,about 600 nanometers). Suitable membrane materials include, forinstance, fibrous webs (e.g., woven or nonwoven), apertured films,foams, sponges, etc., which are formed from polymers such aspolyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetateand ethylene vinyl acetate copolymers.

If desired, the drug delivery assembly may contain additional layers ormaterials that provide various benefits to the resulting transdermalpatch. In one embodiment, for example, the assembly includes an adhesivelayer that can help facilitate the attachment of the patch to a user'sskin during use. Although not required, the adhesive layer is oftendisposed over the reservoir. The adhesive layer typically employs anadhesive coated onto a backing material. The backing may be made of amaterial that is substantially impermeable to the drug compound, such aspolymers, metal foils, etc. Suitable polymers may include, for instance,polyethylene terephthalate, polyvinylchloride, polyethylene,polypropylene, polycarbonate, polyester, and so forth. The adhesive maybe a pressure-sensitive adhesive as is known in the art. Suitableadhesives may include, for instance, solvent-based acrylic adhesives,solvent-based rubber adhesives, silicone adhesives, etc.

A large percentage of receptors to which CBD has affinity to are foundin the skeletal sympathetic nerve terminals. CBD is non-psychoactive andtherefore can be safely give without affects. It has shown to stimulatethe coding through the mRNA expression of a particular enzyme that helpscatalyzes lysine hydroxylation which results in collagen crosslinking inbones. This system is part of the autonomic nervous system which islargely responsible for the body's fight-or-flight response and maintainhomeostasis (psychological balance).

When these receptors get activated by compounds like CBD it triggers andaccelerates the natural healing process. As the aging process occurs,the body's ability to heal fractures slows down drastically. Thehydroxylation of lysine does not occur as readily and affects the amountof crosslinking. In people over 65, fractures account for a third ofthat populations nonfatal injuries and two-thirds of nonfatal care cost.A simple fall can result in serious bone injury. The administration ofnatural extracted or synthetic CBD to older patients who have sufferfrom bone fractures can speed up the healing process and minimizing anyimmobility brought by the fracture. Injections or a patch containing CBDor a synthetic can be administrated at the site to ensure the maximumcompound concentration can be reached. Since the natural deviated CBD isnot readily soluble in water, a greater concentration may be needed toensure that enough gets deliver to the sympathetic nerve endings.

A CBD patch can be produced in a variety of shapes, sizes andconcentration to accommodate the span of the fracture area. Similar topain relief patches, the product will be composed of different layer inwhich the active ingredient is infused into a membrane that will be incontact with the skin. The active ingredient (CBD or synthetic) will beslowly absorbed by the skin into the system and provide a steady releaseof compounds that ensure the activation of bone formation and preventmalformations, which can introduce more structural complications, duringhealing. The patch will have enough active ingredient for a few days(˜3) and easily replaced with a new one. This is noninvasive method oftreatment with low maintenance since it will have a water proof coatingand flexible to accommodate the human structure. As well, the patch canbe also infused with an opium for pain relief. This duel product in onecan aid the heeling process while also offering some pain relief.

CBD cannot only heal bone fractures but also has the potential toincrease the bone mineral density (decreases with age and in certainmedical conditions). The bone mineral density is used as an indicatorfor osteoporosis and fracture risk which increases in age. Injections ororal capsules can be administered for those at risk for low bone mineraldensity to help stimulate bone formation and decrease the likelihood ofa serious bone injury. In medical conditions like in Type 1 DiabetesMellitus (T1DM), bone complications can arise and resulting in low bonemineral density. In particular, women on the onset of menopause (˜40)has an increase difficulty in absorbing calcium for bone formationresulting in fragile bones.

As well, CBD can be used in toothpaste and help strength the root ofteeth.

In another aspect, CBD can be delivered by mixing blended cannabismaterial with fat; identifying cancerous cells in a body; and contactingthe fat cannabis into the body portion with cancerous cells.

In yet another aspect, a method for infusing cannabis with plant orvegetable oil, comprising mixing about 230 grams of cannabis, about ½pound plant or vegetable oil, about 5-7 cups of water, sugar leaf andbud plant parts to form a mixture; boiling the mixture in a magnetic potand decarboxylating the mixture to form a decarboxylated mixture;straining the decarboxylated mixture and after pressing thedecarboxylated mixture dry to form a dry mixture, providing boilingwater to the dry mixture to form an aqueous mixture in a second pot andboiling the aqueous mixture; cooling the aqueous mixture and removing atop oily layer floating to the top of the cooled aqueous mixture;placing the top oily layer in a cup; and placing the cup surrounded by adifferent oil and then boiling the cup in the different oil until waterevaporates leaving oil infused cannabis.

In another aspect, a slow release system using HA and a drug isdisclosed. The HA is cross-linked to provide predetermined dissolutionto release the medication in different layers of HA for release overtime.

In another aspect, CBD can be delivered by mixing blended cannabismaterial with hyaluronic acid (HA); cross-linking the HA to provide aslow release cannabis; identifying cancerous cells in a body; andcontacting the HA infused with cannabis into the body portion withcancerous cells for time release.

In another aspect, oil infused cannabis can be used in one of: candy,baked good, popcorn, gummies, shampoo, conditioner, lotions, soaps,massage oils, lip balm, salad dressings, mayonnaise, margarine, sugarfree food. The oil infused cannabis can also be used in one of: cosmeticgood, medication, aerosol spray. Cannabinoids like cannabiol (CBD)provide two cannabinoid receptors, CB1 and CB2 that are activated byΔ-9-tetrahydrocannabinol (THC), which is the principal psychoactivecompound found in cannabis. In addition, CBD has a low affinity tocannabinoid receptors and hence is non-psychoactive. CBD like othercannabinoids are soluble in non-polar organic solvents. Similarly, CBDcan be infused into oil solvents like avocado oil. Due to the non-watersolubility nature of cannabinoids, they do not interact very well withthe aqueous environment of the blood stream and tissues. To address thisissue, CDB is infused in hyaluronic acid (HA) and the result is placedinside the body or dermally on the skin. As CBD or THC is nothydrophilic, but HA is hydrophilic, HA can bind better to the organ ortissue and then the CDB or THC can interact with the aqueous environmentin the blood stream and tissues. However, this approach should not beused to treat cancer as HA can encourage cancer growth.

The microneedle device fabrication processes avoid exposing a biopolymerand a set of biosubstances carried thereby to processingenvironments/equipment/conditions/energies, reactive species, and/orchemical substances/species associated with conventional micron scalemanufacturing or fabrication processes which would present a significantlikelihood or risk of adversely affecting biosubstance integrity orviability. Multiple embodiments in accordance with the presentdisclosure avoid exposing one or more biosubstances carried by abiopolymer to unnecessarily or undesirably high temperature(s) (e.g., atwhich significant protein denaturation is expected to occur), forinstance, temperatures significantly exceeding room temperature, such astemperatures above approximately 40° C., temperatures aboveapproximately 30° C., or temperatures above or significantly above roomtemperature such as a temperature beyond approximately 27° C.).

In some embodiments, a microneedle forming biopolymer can include bothPEGDA and gelatin (e.g., which can form a biosubstance delivery matrixwithin the microneedles). A support member such as one of more of aglass, quartz, plastic, or other hard material that can be surfacetreated such that (a) a support member surface can firmly couple orchemically bond directly to a layer of microneedle forming biopolymercarried by the support member surface; and (b) microneedles that arefabricated by way of selectively or preferentially cross-linkingportions of the microneedle forming biopolymer layer (such as HA layer)remain firmly coupled or chemically bonded to the support member itself.Hence, in such embodiments, microneedles are not bonded to abiocompatible polymer backing layer carried by a support member, butrather are bonded to one or more surface treated portions of the solidmember itself. Consequently, microneedle fabrication occurs by way ofselectively directing electromagnetic energy through the support memberand into portions of the microneedle forming biopolymer layer carriedthereby (e.g., by way of directing UV light (a) toward, to, and througha set of openings in a photomask disposed adjacent or upon the supportmember; (b) through portions of the support member corresponding to suchopenings; and (c) into corresponding portions of the microneedle formingbiopolymer layer carried by and bonded to the support member). Otherembodiments can include a backing structure having a surface thatincludes (a) a first surface area or region that includes abiocompatible polymer backing layer; and (b) a second surface area orregion that excludes a biocompatible polymer backing layer. Microneedlescan be bonded to and fabricated on each such surface area in a mannerthat is identical, substantially identical, or analogous to thatdescribed above.

Transdermal patches can include reservoir devices, matrix devices,multiple polymer devices, and multilayer matrix systems. The reservoirsystem is a diffusion-controlled system, which contains a drug reservoirwith a rate-controlling polymer membrane. With this device, the membranethat lies between the drug reservoir and the skin controls the rate ofrelease from the drug reservoir to the skin surface. For matrix patches,the active is mixed with or contained in a polymer, the drug is releasedat a rate governed by the components in the matrix. For adrug-in-adhesive matrix, the polymer (in which the drug is dispersed) isan adhesive. The adhesive serves two roles—it acts as the drugreservoir, and it holds the patch on the skin.

Preferably, chemical enhancers, iontophoresis, and non-cavitationalultrasound can be used to increase skin permeability. Other transdermaldelivery systems can target the stratum corneum using microneedles,thermal ablation, microdermabrasion, electroporation, and cavitationalultrasound to enable more effective transdermal delivery, while stillprotecting the deeper tissues.

Other skin permeabilization techniques, including low-frequencysonophoresis and electroporation, have been studied further to refinetheir role in enhancing delivery through skin. Modulated delivery (i.e.,controlled amount of dose) is possible using iontophoresis when anappropriate amount of current is applied over a stipulated timeduration. Physical enhancement techniques have thus expanded the scopeof transdermal delivery and have a promising future

The micro-needles on the patch create micrometre-sized porous channelsin the skin, thereby, enabling rapid drug delivery. Because the needleshafts are approximately 600 μm in length, they do not cause anyperceptible pain. The reservoir system in the patch acts as channels fordrugs to be encapsulated in the backing layers, circumventing thepremature closure of miniaturized pores created by the microneedles andensuring continued drug permeation.

One embodiment forms microneedles, which are less than 0.5 mm high orsmaller, from a hydrogel of biocompatible polymers that can safelydeliver constant doses of the drug. The microneedles are hard and sharpwhen dry, but rapidly hydrate when inserted into the skin. The swollenhydrogel projections create a continuous aqueous pathway between theexternal environment and dermal microcirculation enabling controlleddelivery of the API. In other embodiments, the microneedle arrayconsists of a sheet arrayed with 100-2000 μm projections made ofpolysaccharides. The drug is delivered into the body by simply attachingthe sheet onto the skin. These projections dissolve in the skin withinminutes as the drug is delivered.

In one embodiment, THC can be used to treat glioblastoma multiforme(GBM), a malignant primary brain tumor. In one embodiment, the THCadministered composition is as follow: 96.5% THC, 1.5% of Δ8-THC, 0.5%butyl-THC, and propyl-THC. The patient first undergoes a surgicalprocedure to make a cavity in the brain, and then THC treatment is asfollows:

-   -   1. A cavity and incision are made surgically near tumor tissue    -   2. A silastic infusion catheter is inserted inside cavity,        portion of the catheter will be left accessible on the outside    -   3. Connected to catheter is a subclavicular reservoir    -   4. 100 mg (THC solution)/ethanol is dissolved in 30 mL        physiological saline solution with 0.5% weight/volume human        serum albumin    -   5. Syringe pump transfers 0.3 mL/min of the THC solution to the        subcutaneous reservoir.

On the first day the dosage given is 20-40 depending on side effectsobserved. The amount can be slowly increased to 80-180 μg per day for2-5 days. THC solution is administered on an average of 15 days perpatient.

Due to the chemical structure of cannabinoids, they do not easilyinteract with the hydrophilic nature of tissues and cell membranes. As aresult they do not travel far in deep tissues if inject directly intothe blood stream and therefore not a very effective method. A moreviable option is applying directly to the needed area through the usageof a catheter or similar mechanism. This would allow a greaterconcentration to be absorbed by cells. This is easier when the target isare easily located and accessible. As well, some synthesized cannabinoidcompounds such as cannabinoid quinones have proven to be more watersoluble than their naturally occurring counterparts. As a result it willbe more quickly absorbed by the tissues and needing less of the activeingredient. An ideal synthetic compound would have the therapeuticproperties observed in studies, have no psychoactive affects (noaffinity for CB1 receptor) and high human absorption.

Cannabinoids may cause antitumor effects by various mechanisms,including induction of cell death, inhibition of cell growth, andinhibition of tumor angiogenesis invasion and metastasis. Cannabinoidsappear to kill tumor cells but do not affect their nontransformedcounterparts and may even protect them from cell death. For example,these compounds have been shown to induce apoptosis in glioma cells inculture and induce regression of glioma tumors in mice and rats, whilethey protect normal glial cells of astroglial and oligodendrogliallineages from apoptosis mediated by the CB1 receptor. The effects ofdelta-9-THC and a synthetic agonist of the CB2 receptor wereinvestigated in HCC. Cannabinoids were shown to trigger cell deaththrough stimulation of an endoplasmic reticulum stress pathway thatactivates autophagy and promotes apoptosis. CBD induced programmed celldeath, independent of the CB1, CB2, or vanilloid receptors. CBDinhibited the survival of both estrogen receptor-positive and estrogenreceptor-negative breast cancer cell lines, inducing apoptosis in aconcentration-dependent manner while having little effect onnontumorigenic mammary cells.

Similar administration can be given in breast cancer treatment. In vivoand vitro studies have demonstrated the effectiveness of CBD andsynthetic compounds with affinity to CB2 receptors to shrink breasttumors, and obstruct growth and metastasis in mice models. Thesecompounds have demonstrated a specificity to target cancer cells andcytotoxicity test have shown no damage or toxics in other organs in thebody. CBD can be administered after lumpectomy (removal of breast cancertissue) to target any remaining cancer tissue and prevent metastasis.Administration is:

-   -   1. General anesthetic is administered, incision is made in the        breast near where tumor was located and cavity is prepared    -   2. Small balloon-catheter is used and the soft balloon portion        is inserted into cavity, Tip of catheter tube is left outside        near incision. Balloon is filled with saline solution and        secured    -   3. Exposed catheter is connected to syringe pump and appropriate        dosage of CBD or synthetic dissolved in physiological saline        solution    -   4. Syringe pump delivers final solution at desired rate for the        duration of treatment time

One use for medicinal cannabis in cancer treatment is for painmanagement. A study compared the therapeutic usage and effects of smokedmarijuana and orally administered THC (dronabinol). The sensitivity andtolerance to pain were measured by having the participants take thecold-pressor test after administration. It was concluded that bothmarijuana and dronabinol decreased pain sensitivity. In dronabinol,however the decreased pain sensitivity affects were felt at a latertime. On the average, with smoked cannabis the pain reduction affectswere felt 15 minutes whereas with dronabinol it took 180 minutes afteradministration. However, dronabinol affects lasted longer than smokedmarijuana. The orally administered THC used size 00 opaque capsules witha dosage of either 10 mg or 20 mg. Lactose was used as the filler in thecapsules. Orally taken dronabinol can be an effective method to delivercannabis material without harmful side effects. Additionally, there areavocado oil supplements in capsule form available for people. Theavocado infused cannabis could similarly be administered to peopleundergoing cancer treatments to treat their pain and other side effects.This option could make it easier for patients to intake cannabiscompounds during treatment if they cannot tolerant other methods.

Cannabinoids may also be used in the treatment of glaucoma, which isdamage in the optic nerves as a result of increased eye pressure(intraocular pressure). While marijuana decreases intraocular pressurein both healthy and sickly eyes, this decrease in pressure can result inlower blood delivery to the optic nerves cause damage. Oral capsules oreye drops are options for administration. In particular, eye dropletscontaining THC and other cannabinoids have been investigated and havethe potential to decrease eye pressure. Due to the high hydrophobicnature of cannabinoids, it is not easily absorbed by the eye. This iscompensated by adding HA into the eye droplets formation which offers:

-   -   soluble in an aqueous environment (eye membrane and tissue) and        therefore lower concentration of active ingredient is needed    -   reduce optic nerve damage    -   Longer lasting affects

Administration of eye drop containing HA and cannabinoids is as fallow:

-   -   1. Ensure clean environment, tilt head and look upward with both        eyes    -   2. Pull down lower eye lid slightly while holding tip of eye        drop bottle near eye with the second hand    -   3. Applied enough pressure to bottle to administered one drop        into the eye, blink and close eye for a few seconds    -   4. Repeats for second eye

The resulting oil with cannabis is usable immediately and the effectsare long lasting and near instant if used sublingually. The Oil is ahealthy alternative to butter and all types of other oils, which allowsvegans to enjoy food. It can be eaten directly or put into many productsincluding hard candies, baked goods (brownies, cookies), popcorn,gummies, shampoo, conditioner, lotions, soaps, massage oils, lip balm,salad dressings, mayonnaise, and margarine. The oil can be used in sugarfree line of products to make them friendly for diabetic patients.

Oil was originally, and still is, extracted for cosmetic use because ofits very high skin penetration and rapid absorption. After extraction,the oil with added cannabis for application in skin care products isrefined, bleached, and deodorized, resulting in an odorless yellow oil.Like extra virgin olive oil, cold-pressed oil is unrefined and soretains the flavor and color characteristics of the fruit flesh.

The solution can be used on skin. Topically the cannabis infused oil isrubbed onto an affected area and because this contains no alcohol it ispossible to put it on slightly open cuts without burning or irritation.Oil acts as a natural anti-inflammatory and contains multiple vitamins,minerals, antioxidants and when used in combination with cannabis hasshown great success in the rate of healing. This is a holisticalternative to the multitude of harmful by-products found in many otheritems currently used by consumers.

The CBD can be used as a pharmaceutical formulation that are packagedfor delivery in the form of a gel, a tablet, a liquid, a capsule or forvaporization. More preferably the combination of cannabinoids to be usedas a pharmaceutical formulation are packaged for delivery sublinguallyor buccally, preferably as a sublingual or buccal spray. Advantageouslythe pharmaceutical formulation further comprises one or more carriersolvent/s. Preferably the carrier solvents are ethanol and/or propyleneglycol. More preferably the ratio of ethanol to propylene glycol isbetween 4:1 and 1:4. More preferably still the ratio is 1:1.

The administration of a combination of cannabinoids such as THC and CBDcould be administered to a patient either at the same time, wherein thecannabinoids would be contained in the same formulation. Thecannabinoids could also be administered at separate times for example; aformulation containing CBD could be administered to a patient at a fixedtime prior to a formulation containing THC in order to ameliorate someof the side effects of THC, which CBD is known to improve or vice versa.The two cannabinoids could also be administered consecutively to apatient if required.

Preferably the invention provides a combination of cannabinoids, whichare present as one or more cannabis based medicine extract/s (CBME/s).In one embodiment the CBME/s are produced by extraction withsupercritical or subcritical CO2. In an additional embodiment the CBME/sare produced by extraction from plant material by volatilization with aheated gas. Preferably the CBME/s contain all of the naturally occurringcannabinoids in the plant material. Alternatively synthetic or highlypurified isolates of the cannabinoids can be used.

The arthritis treatment can include administering a combination ofcannabinoids x and y, where x is selected from the group consisting ofcannabidiol (CBD) and cannabidivarin (CBDV) and where y is selected fromthe group consisting of delta-9-tetrahydrocannabinol (THC) andtetrahydrocannabinovarin (THCV), wherein the ratio of x:y by weight isless than or equal to 19:1.

THC and CBD compounds are activated in order to have an affinity toreceptors like CB1 and CB2 and an effect in people. In their naturalform in raw cannabis, they are found as cannabinolic acids, THCA andCBDA. Both have an attached carboxylic acid on one of the fused rings.To activate, the compounds undergo decarboxylation to remove thecarboxyl group, which can be done by applying high amounts of heat. Thisresults in the final THC and CBD products and the release of one CO2molecule. When cannabis material is smoked, the compounds undergo thiscarboxyl group loss as it is being consumed by the flame. Fornon-smoking application such as oral or injectable administration, thisneeds to be part of the processing and preparation of the product. Inthe case of cannabis infused fruit oil, the mixing of the two materialsis carried at high temperatures, 100° C., which serves as a way for thecannabinoid to lose the carboxylic acid and to suspended the compoundsin the solvent.

The cannabis infused oil can be used in an aerosol spray. FIG. 3 showsdispensing device for use with a pressurized aerosol-dispensingcontainer 1. A can 1 contains the cannabis infused oil as the product 2,and compressed gas propellant 3 to propel the oil 2 through a tube. Whenthe user presses on the dispensing head, compressed gas drives the oilthrough the tube where the oil exits at a nozzle of a spray head 4 as amist of cannabis infused oil spray 6. Super saturation can be applied astransdermal spray, where supersaturated states are generated becausevolatile components (e.g., ethanol or isopropanol) evaporate after thespray is applied to skin, with consequent enhancement in skin flux.

In another embodiment, cannabis can be used in an electronic cigarette.An electronic cigarette battery with threading (such as the eGo-Twist orVision Spinner) and a dry herb cartridge can be heated using a variablevoltage battery so that the smoker can fine-tune the temperature tohis/her liking. The vape pen herb cartridges will combust the herb, notvaporize it. A dry herb cartridge attachment will turn your e-cigaretteinto an electric pipe (or e-blunt). For vaporization, a laser withsuitable power supply is used.

For inhalation, the formulations of the present invention may bedelivered via any inhalation methods known to those skilled in the art.Such inhalation methods and devices include, but are not limited to,metered dose inhalers with propellants such as CFC or HFA or propellantsthat are physiologically and environmentally acceptable. Other includeddevices are breath-operated inhalers, multidose dry powder inhalers andaerosol nebulizers. One preferred way of administering the formulationsof the invention is by using conventional actuators. The term “actuator”as used in the present invention includes all types of actuatorspresently available including but not limited to standard metered doseinhalers or breath operated inhalers. In another embodiment of theinvention, administration is effected by a means of a pump orsqueeze-actuated nebulizer. In more preferred embodiments of theinvention administration is effected by means of a metered dose inhaleror an aerosol dispenser.

Formulations of the present invention may conveniently be present inunit dosage form and may be prepared by conventional pharmaceuticaltechniques as discussed above. Such techniques include the step ofbringing into association the THC moiety and the pharmaceuticalcarrier(s) or excipient(s) In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product. While magnetic cook plate has beenmentioned, a crockpot or a gas stove can be used. Depictions of variousexemplary cannabis cookware and accessories as may be used withexemplary embodiments of the claimed invention are included in FIG. 3.

Avocados are one of the great cancer fighting foods, rich in amultiplicity of nutrients, including many potent anti-oxidants andphytochemicals as well as vitamins, minerals, fiber and monounsaturatedhealthy fats. Phytochemicals (plant chemicals) are defined as bioactivenon-nutrient plant compounds in fruits, vegetables, grains, and otherplant foods that have been linked to reducing the risk of major chronicdiseases including cancer. Antioxidants and Phytochemicals found inavocados include:

Carotenoids: beta carotene, alpha carotene, zeaxanthin shown to inhibitthe growth of prostate, breast and head and neck (oral) cancers.

Vitamin E is an antioxidant. Its role in cancer prevention is ambiguousdue to several conflicting studies. Research suggests that the Vitamin Efound in its natural form in foods such as avocados is indeedprotective, while synthetic Vitamin E (alpha tocopherol acetate)supplements do not show this protective effect. The Nurses Health Studystudied 83,234 women at baseline and sought to assess the incidence ofbreast cancer during a 14-year follow-up. The study showed thatpre-menopausal women with a family history of breast cancer who consumedthe highest quantity of vitamin E enjoyed a 43 percent reduction inbreast cancer incidence compared to only a 16 percent risk reduction forwomen without a family history of breast cancer. The data indicates thatsome of the vitamin E compounds in food may account for the dramaticreductions in breast cancer incidence when dietary intake levels ofvitamin E are measured.

Lutein: women with increased intake of lutein in their diets have beenshown to have lower rates of breast cancer (Freudenheim J L, Marshall JR, Vena J E et al: Premenopausal breast cancer risk and intake ofvegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88(6):340-348.) Lutein is also found in high quantities in kale,broccoli and spinach.

Glutathione Glutathione is the body's master antioxidant. When liverglutathione levels rise, the liver is able to more effectively detoxifythe body and protect the cells from oxidative stress. Whey protein alsoincreases the glutathioine levels of healthy cells while decreasing theglutathione levels of cancer cells.

Oleic Acid Avocados are also a source of fiber and oleic acid, a healthymonounsaturated fat. Oleic acid helps to lower unhealthy LDL plaqueforming cholesterol. Increasing healthy dietary fats. Loweringcholesterol and body fat not only lead to reduced risk of cardiovasculardisease but also lead to reduced inflammation and reduced cancer risk.

Oleic acid, the primary fat in avocados has been shown to offersignificant protection against breast cancer. Women eating a diet richin oleic acid have shown decreased rates of breast cancer. Oleic acid isalso found in olives, olive oil, walnuts, almonds and pine nuts.

The phytochemicals listed above are all better absorbed in the presenceof healthy fats and oils. Therefore the oleic acid in avocados not onlyhelps the body to absorb and utilize the antioxidants also found withinthe avocado itself but contributes to the absorption of phytochemicalscontained in other fruits and vegetables eaten at the same meal.Nature's design provides for optimum utilization of nutrients. One cupof Avocados also contains as much as 30 percent of your daily fiberintake as well as significant amounts of Vitamin K, Potassium, Folate,and Vitamin B6 all important to normal healthy cell function and cancerprevention.

The cannabinoids in marijuana slow cancer growth, inhibit formation ofnew blood cells that feed a tumor, and help manage pain, fatigue,nausea, and other side effects when cancer cells are exposed totetrahydrocannabinol (THC), the principal psychoactive ingredient ofmarijuana. THC and other marijuana-derived compounds, known as“cannabinoids,” are effective not only for cancer-symptom management(nausea, pain, loss of appetite, fatigue), they also confer a directantitumoral effect.

In one treatment scenario, THC in oil slows tumor growth in common lungcancer and significantly reduces the ability of the cancer to spread.THC selectively targets and destroys tumor cells while leaving healthycells unscathed. Conventional chemotherapy drugs, by contrast, arehighly toxic; they indiscriminately damage the brain and body. Theavocado based cannabinoids represent a class of anticancer drugs thatretard cancer growth, inhibit angiogenesis [the formation of new bloodcells that feed a tumor] and the metastatic spreading of cancer cells.

In another scenario, CBD is used as an inhibitor of breast cancer cellproliferation, metastasis, and tumor growth. The CBD kills breast cancercells and destroys malignant tumors by switching off expression of theID-1 gene, a protein that appears to play a major role as a cancer cellconductor. The ID-1 gene is active during human embryonic development,after which it turns off and stays off. But in breast cancer and severalother types of metastatic cancer, the ID-1 gene becomes active again,causing malignant cells to invade and metastasize. The oil withcannabidiol, a potent antitumoral compound in its own right, actssynergistically with various anti-cancer pharmaceuticals, enhancingtheir impact while cutting the toxic dosage necessary for maximumeffect.

Cannabis contains over 400 cannabinoid compounds and produces a widespectrum of central and peripheral effects including alterations incognition and memory, analgesic, anticonvulsive, and anti-inflammatoryactivities, and alleviation of intraocular pressure, nausea, and pain.It has also been demonstrated that cannabinoids have direct antitumoractivity as well as immune response-associated antitumor activity. Theantitumor activities involve different physiological pathways. Forexample, cannabinoids signal apoptosis by a pathway involvingcannabinoid receptors, sustained ceramide accumulation, andRaf1/extracellular signal-regulated kinase activation.

The psychotropic principle of cannabis is delta-9-tetrahydrocannabinol(delta-9-THC), however, numerous medicinal properties of cannabis arethought to be associated with the acid metabolites of delta-9-THC, whichshow little or no psychoactivity. The physiological effects of thecannabinoids have been attributed to both receptor-mediated andnon-receptor-mediated activities. Two types of cannabinoid receptors,CB1 and CB2, have been cloned in humans. The central cannabinoidreceptor, CB1, is predominantly located in the central nervous system,although CB1 has also been detected in the gastrointestinal tract andother peripheral tissues. The CB2 receptor is predominantly found in theimmune system. These receptors are members of the G-protein-coupledreceptor superfamily (Pertwee, R. G., Pharmacol. Ther., 74(2): 129-180,1997). CB1 and CB2 receptors have been demonstrated in prostate tissue.Recently, Ruiz-Llorente et al. (The Prostate, 54:95-102, 2003) haveprovided evidence that the CB1 receptor is functionally active in thehuman prostate gland.

The delta-9-THC inhibits specific binding of dihydroxytestosterone tothe androgen receptor in the prostate gland, potentially regulating theserum levels of many sex hormones, thereby having an indirectantitumorigenic effect. Melck et al. (Endocrinology, 141:118-126, 2000)have shown that endocannabinoids, i.e. naturally occurring cannabinoids,inhibit prolactin-induced proliferation in the prostate cell line,DU-145, by inhibiting expression of prolactin receptors via aCB1-dependent mechanism. Ruiz et al. (FEBS Letters, 458:400-404, 1999)have shown that delta-9-THC causes apoptosis in the prostate cell line,PC-3. The apoptotic effect was similar to that apoptotic effecttypically associated with ceramide accumulation. Ceramide has beenimplicated as an important second messenger regulating cell death. Inprostate cells, ceramide has been shown to mediate apoptosis.

The analgesic and anti-inflammatory properties of delta-9-THC may be dueto its acid metabolites (Burstein, S. H., Pharmacol. Ther., 82(1):87-96,1999). Acid metabolites may result in an inhibition of eicosanoidsynthesis; eicosanoids are mediators of inflammation. It has beenpostulated that the analgesic and anti-inflammatory properties are dueto cannabinoid acids impacting on the arachidonic acid cascade by eithercausing an accumulation of free arachidonic acid or by inhibiting thesynthesis of COX-2. COX-2 products are associated with inflammation. Asa potential analgesic and anti-inflammatory therapeutic, it is ofinterest that chronic users of cannabis who are exposed to high bloodlevels of the delta-9-THC metabolite, delta-8-THC-11-oic acid, appear tobe free from non-steroidal anti-inflammatory drug-type toxicity. Thismay be due in part to a selective inhibition of COX-2.

The prior art indicates that pharmaceuticals, phytochemicals, andnutraceuticals are available for treating disorders of the prostate byproviding antioxidant activity, anti-inflammatory activity, and/orantitumorigenic activity. However, it is a concern that pharmaceuticalsare expensive, have undesirable side effects, and generally requiresystemic application. It is a further concern that phytochemicals orextracts obtained from various plant sources can potentially containtoxins, may not be standardized, or may interact with other medications.Therefore, it would be advantageous to provide natural compositions fortreatment of prostate disorders that lack toxic properties and thatcontain desirable therapeutically effective activities such asanti-inflammatory, antioxidant, as well as antitumorigenic activities.In this regard, extracts of cannabis plant material have beenestablished to be non-toxic, and to have anti-inflammatory, antioxidant,and antitumorigenic properties in prostate tissue. Given the lack oftoxicity of cannabinoids and the ability of the cannabinoids to protectprostate health by a myriad of distinct receptor-mediated andreceptor-independent pathways by providing antioxidant protection,altering the conversion of testosterone to dihydroxytestosterone,inhibiting the binding of dihydroxytestosterone to androgen receptors,inducing apoptosis, and decreasing cellular proliferation, compositionscontaining cannabis extracts provide a therapeutically effective meansof treating prostate disorders in patients in need thereof.

The phytocannabinoids described in the present application are listedbelow along with their standard abbreviations.

CBC Cannabichromene

CBCV Cannabichromenic acid

CBD Cannabidiol

CBDA Cannabidiolic acid

CBDV Cannabidivarin

CBG Cannabigerol

CBGV Cannabigerol propyl variant

CBL Cannabicyclol

CBN Cannabinol

CBNV Cannabinol propyl variant

CBO Cannabitriol

THC Tetrahydrocannabinol

THCA Tetrahydrocannabinolic acid

THCV Tetrahydrocannabivarin

THCVA Tetrahydrocannabivarinic acid

The table above is not exhaustive and merely details the cannabinoidswhich are identified in the present application for reference. So farover 60 different cannabinoids have been identified and thesecannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids.

“Phytocannabinoids” are cannabinoids that originate from nature and canbe found in the cannabis plant. The phytocannabinoids can be isolatedcannabinoids or present as a botanical drug substance.

An “isolated cannabinoid” is defined as a phytocannabinoid that has beenextracted from the cannabis plant and purified to such an extent thatall the additional components such as secondary and minor cannabinoidsand the non-cannabinoid fraction have been removed.

A “botanical drug substance” or “BDS” is defined in the Guidance forIndustry Botanical Drug Products Draft Guidance, August 2000, USDepartment of Health and Human Services, Food and Drug AdministrationCentre for Drug Evaluation and Research as: “A drug derived from one ormore plants, algae, or microscopic fungi. It is prepared from botanicalraw materials by one or more of the following processes: pulverization,decoction, expression, aqueous extraction, ethanolic extraction or othersimilar processes.” A botanical drug substance does not include a highlypurified or chemically modified substance derived from natural sources.Thus, in the case of cannabis, BDS derived from cannabis plants do notinclude highly purified Pharmacopoeial grade cannabinoids.

“Endocannabinoids” are the cannabinoids that are produced endogenouslyby human or animal bodies. Up or down regulation of the endocannabinoidsystem may be useful in the treatment of some diseases or conditions.

“Synthetic cannabinoids” are compounds that have a cannabinoid-likestructure yet are manufactured using chemical means. Depending on themethod of manufacture the synthetic cannabinoid may comprise a racemicmixture of cannabinoids, in contrast to an isolated cannabinoid whichwill be a single enantiomer.

Phytocannabinoids can be found as either the neutral (decarboxylatedform) or the carboxylic acid form depending on the method used toextract the cannabinoids. For example it is known that heating thecarboxylic acid form will cause most of the carboxylic acid form todecarboxylate into the neutral form.

Phytocannabinoids can also occur as either the pentyl (5 carbon atoms)or propyl (3 carbon atoms) variant. Initially it was thought that thepropyl and pentyl variants would have similar properties, however recentresearch has found that this may not be true. For example thephytocannabinoid THC is known to be a CB1 receptor agonist whereas thepropyl variant THCV has been discovered to be a CB1 receptor antagonistmeaning that it has almost opposite effects.

In the present invention a BDS is considered to have two components: thephytocannabinoid-containing component and the non-phytocannabinoidcontaining component. Preferably the phytocannabinoid-containingcomponent is the larger component comprising greater than 50% (w/w) ofthe total BDS and the non-phytocannabinoid containing component is thesmaller component comprising less than 50% (w/w) of the total BDS.

The amount of phytocannabinoid-containing component in the BDS may begreater than 55%, through 60%, 65%, 70%, 75%, 80% to 85% or more of thetotal extract. The actual amount is likely to depend on the startingmaterial used and the method of extraction used.

The “principle phytocannabinoid” in a BDS is the phytocannabinoid thatis present in an amount that is higher than that of the otherphytocannabinoids. Preferably the principle phytocannabinoid is presentin an amount greater than 40% (w/w) of the total extract. Morepreferably the principle phytocannabinoid is present in an amountgreater than 50% (w/w) of the total extract. More preferably still theprinciple phytocannabinoid is present in an amount greater than 60%(w/w) of the total extract.

The amount of the principle phytocannabinoid in the BDS is preferablygreater than 75% of the phytocannabinoid-containing fraction, morepreferably still greater than 85% of the phytocannabinoid-containingfraction, and more preferably still greater than 95% of thephytocannabinoid-containing fraction.

In some cases, such as where the principle cannabinoid is either CBDV orTHCVA the amount of the principle phytocannabinoid in the BDS is lower.Here the amount of phytocannabinoid is preferably greater than 55% ofthe phytocannabinoid-containing fraction.

The “secondary phytocannabinoid/s” in a BDS is the phytocannabinoid/sthat is/are present in significant proportions. Preferably the secondaryphytocannabinoid is present in an amount greater than 5% (w/w) of thetotal extract, more preferably greater than 10% (w/w) of the totalextract, more preferably still greater than 15% (w/w) of the totalextract. Some BDS's will have two or more secondary phytocannabinoidsthat are present in significant amounts. However not all BDS's will havea secondary phytocannabinoid. For example CBG BDS does not have asecondary phytocannabinoid in its extract.

The “minor phytocannabinoid/s” in a BDS can be described as theremainder of all the phytocannabinoid components once the principle andsecondary phytocannabinoids are accounted for. Preferably the minorphytocannabinoids are present in total in an amount of less than 10%(w/w) of the total extract, more preferably still less than 5% (w/w) ofthe total extract, and most preferably the minor phytocannabinoid ispresent in an amount less than 2% (w/w) of the total extract.

Typically the non-phytocannabinoid containing component of the BDScomprises terpenes, sterols, triglycerides, alkanes, squalenes,tocopherols and carotenoids.

These compounds may play an important role in the pharmacology of theBDS either alone or in combination with the phytocannabinoid.

The “terpene fraction” may be of significance and can be broken down bythe type of terpene: monoterpene or sesquiterpene. These terpenecomponents can be further defined in a similar manner to thecannabinoids.

The amount of non-phytocannabinoid containing component in the BDS maybe less than 45%, through 40%, 35%, 30, 25%, 20% to 15% or less of thetotal extract. The actual amount is likely to depend on the startingmaterial used and the method of extraction used.

The “principle monoterpene/s” in a BDS is the monoterpene that ispresent in an amount that is higher than that of the other monoterpenes.Preferably the principle monoterpene/s is present in an amount greaterthan 20% (w/w) of the total terpene content. More preferably theprinciple monoterpene is present in an amount greater than 30% (w/w) ofthe total terpene content, more preferably still greater than 40% (w/w)of the total terpene content, and more preferably still greater than 50%(w/w) of the total terpene content. The principle monoterpene ispreferably a myrcene or pinene. In some cases there may be two principlemonoterpenes. Where this is the case the principle monoterpenes arepreferably a pinene and/or a myrcene.

The “principle sesquiterpene” in a BDS is the sesquiterpene that ispresent in an amount that is higher than all the other terpenes.Preferably the principle sesquiterpene is present in an amount greaterthan 20% (w/w) of the total terpene content, more preferably still tgreater than 30% (w/w) of the total terpene content. The principlesesquiterpene is preferably a caryophyllene and/or a humulene.

The sesquiterpene components may have a “secondary sesquiterpene”. Thesecondary monoterpene is preferably a pinene, which is preferablypresent at an amount greater than 5% (w/w) of the total terpene content,more preferably the secondary terpene is present at an amount greaterthan 10% (w/w) of the total terpene content.

The secondary sesquiterpene is preferably a humulene which is preferablypresent at an amount greater than 5% (w/w) of the total terpene content,more preferably the secondary terpene is present at an amount greaterthan 10% (w/w) of the total terpene content.

Alternatively botanical extracts may be prepared by introducing isolatedphytocannabinoids into a non-cannabinoid plant fraction as can beobtained from a zero cannabinoid plant or a CBG-free BDS.

In one implementation, a cannabis plant extract comprising aphytocannabinoid containing component and a non-phytocannabinoidcontaining component, is infused or mixed in oil for use in medicine,wherein the phytocannabinoid containing component comprises at least 50%(w/w) of the cannabis plant extract and the non-phytocannabinoidcontaining component comprises a monoterpene fraction and asesquiterpene fraction, in which a principle monoterpene sub-fraction isselected from myrcenes or pinenes and a principle sesquiterpenesub-fraction is selected from caryophyllenes or humulenes.

In one implementation, a cannabis plant extract comprising aphytocannabinoid containing component and a non-phytocannabinoidcontaining component, is infused or mixed in oil for use in medicine,wherein the phytocannabinoid containing component comprises at least 50%(w/w) of the cannabis plant extract and the non-phytocannabinoidcontaining component comprises a monoterpene fraction and asesquiterpene fraction, in which a principle monoterpene sub-fraction isselected from myrcenes or pinenes and a principle sesquiterpenesub-fraction is selected from caryophyllenes or humulenes.

Such cannabis infused oil can be used for treating a patient byadministering a therapeutically effective amount of a cannabis plantextract comprising a phytocannabinoid containing component and anon-phytocannabinoid containing component, wherein the phytocannabinoidcontaining component comprises at least 50% (w/w) of the cannabis plantextract and the non-phytocannabinoid containing component comprises amonoterpene fraction and a sesquiterpene fraction, in which a principlemonoterpene sub-fraction is selected from myrcenes or pinenes and aprinciple sesquiterpene sub-fraction is selected from caryophyllenes orhumulenes to the patient.

Preferably principle monoterpene sub-fraction comprises myrcenes and thesecondary monoterpene sub-fraction comprises pinenes. In anotherembodiment the principle monoterpene sub-fraction are both myrcenes andpinenes.

Preferably the principle sesquiterpene sub-fraction comprisescaryophyllenes and secondary sesquiterpene sub-fraction compriseshumulenes.

Preferably the principle phytocannabinoid is selected from the groupconsisting of: THCV, CBDV, CBGV, THCVA, THCA, CBDA, CBG, THC, CBD andCBC.

Preferably the non-phytocannabinoid containing component furthercomprises one or more compounds from the group consisting of:diterpenes; triterpenes; sterols; triglycerides; alkanes; squalenes;tocopherols; and carotenoids.

In one embodiment the cannabis plant extract comprises the principlephytocannabinoid CBG and the phytocannabinoid containing componentcomprises 61-75% (w/w) of the cannabis plant extract. Preferably theextract further comprises greater than 88% (w/w) CBG of the totalphytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid THC and the phytocannabinoid containingcomponent comprises 77-94% (w/w) of the cannabis plant extract.Preferably the extract further comprises 78-95% (w/w) THC of the totalphytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid CBD and the phytocannabinoid containingcomponent comprises 76-96% (w/w) of the cannabis plant extract.Preferably the extract further comprises 72-88% (w/w) CBD of the totalphytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid CBC and the phytocannabinoid containingcomponent comprises 49-60% (w/w) of the cannabis plant extract.Preferably the extract further comprises 71-87% (w/w) CBC of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoids CBD and CBL. More preferably still theCBD comprises 6.5-8% (w/w) of the total phytocannabinoid fraction andthe CBL comprises 5.8-7.1 (w/w) of the total phytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid THCV and the phytocannabinoid containingcomponent comprises 74-90% (w/w) of the cannabis plant extract.Preferably the extract further comprises 71-87% (w/w) THCV of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoid THC. More preferably still the THCcomprises 14.8-18% (w/w) of the total phytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid CBDV and the phytocannabinoid containingcomponent comprises 64-78% (w/w) of the cannabis plant extract.Preferably the extract further comprises 52-64% (w/w) CBDV of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoids CBD and CBCV. More preferably still theCBD comprises 22.4-27.4% (w/w) of the total phytocannabinoid fractionand the CBCV comprises 5.5-6.7 (w/w) of the total phytocannabinoidfraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid CBGV and the phytocannabinoid containingcomponent comprises 54-66% (w/w) of the cannabis plant extract.Preferably the extract further comprises 68-84% (w/w)

CBGV of the total phytocannabinoid fraction. More preferably the extractfurther comprises the secondary phytocannabinoid CBG. More preferablystill the CBG comprises 19-23% (w/w) of the total phytocannabinoidfraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid THCA and the phytocannabinoid containingcomponent comprises 54-66% (w/w) of the cannabis plant extract.Preferably the extract further comprises 71-86% (w/w) THCA of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoid THC. More preferably still the THCcomprises 13.4-16.4% (w/w) of the total phytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid CBDA and the phytocannabinoid containingcomponent comprises 71-86% (w/w) of the cannabis plant extract.Preferably the extract further comprises 78-86% (w/w) CBDA of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoid CBD. More preferably still the CBDcomprises 6.1-7.5% (w/w) of the total phytocannabinoid fraction.

In a further embodiment the cannabis plant extract comprises theprinciple phytocannabinoid THCVA and the phytocannabinoid containingcomponent comprises 62-75% (w/w) of the cannabis plant extract.Preferably the extract further comprises 53-65% (w/w) THCVA of the totalphytocannabinoid fraction. More preferably the extract further comprisesthe secondary phytocannabinoid THCV. More preferably still the THCVcomprises 17.3-21.2% (w/w) of the total phytocannabinoid fraction.

In a fourth aspect of the present invention there is provided one ormore phytocannabinoids, either in an isolated form or in the form of abotanical drug substance (BDS), as a prophylactic or in the treatment ofcancer

In a fifth aspect of the present invention there is provided one or morephytocannabinoids taken from the group selected from: THCV, CBDV, THCVA,THCA, CBDA, CBD, CBG, and CBC, for use in the treatment of prostatecancer, wherein the THCVA is present as an isolated phytocannabinoid,the THCA, CBDA CBD, CBG or CBC are present in the form of a BDS, and theTHCV or CBDV are present in either an isolated form or in the form of aBDS.

In accordance with a sixth aspect of the present invention there isprovided the use of one or more phytocannabinoids taken from the groupselected from: THCV, CBDV, THCVA, THCA, CBDA, CBD, CBG, and CBC, for usein the manufacture of a medicament to treat prostate cancer, wherein theTHCVA is present as an isolated phytocannabinoid, the THCA, CBDA CBD,CBG or CBC are present in the form of a BDS, and the THCV or CBDV arepresent in either an isolated form or in the form of a BDS.

In accordance with a seventh aspect of the present invention there isprovided a method of treating a patient with prostate cancer comprisingadministering an effective amount of one or more phytocannabinoids,selected from the group consisting of: THCV, CBDV, THCVA, THCA, CBDA,CBD, CBG, and CBC, wherein, where present, the THCVA is present as anisolated phytocannabinoid, the THCA, CBDA, CBD, CBG or CBC are presentin the form of a BDS, and the THCV or CBDV are present in either anisolated form or in the form of a BDS to the patient.

In one embodiment the one or more phytocannabinoids are propyl variantphytocannabinoids.

In a second embodiment the one or more phytocannabinoids are in an acidform.

In a further embodiment the one or more phytocannabinoids are in aneutral or decarboxylated form.

In a preferred embodiment the phytocannabinoid is CBG and is in the formof a BDS.

Preferably the prostate cancer is hormone-sensitive prostate cancer.

In another embodiment the phytocannabinoid is THCVA in an isolated form.

In a further embodiment the prostate cancer is hormone-insensitiveprostate cancer and the phytocannabinoid is CBD and is in the form of aBDS or the phytocannabinoid is CBDV and is in the form of a BDS.

Preferably the one or more phytocannabinoids are used in combination oras an adjunct therapy with a chemotherapeutic agent and/or ananti-androgen.

Preferably the chemotherapeutic agent is a mitotic inhibitor. Themitotic inhibitor is preferably from the taxane drug class. Morepreferably the mitotic inhibitor taken from the taxane drug class istaken from the group: docetaxel; larotaxel; ortataxel; paclitaxel; andtesetaxel.

The one or more phytocannabinoids can be infused in oil or PVA orsynthetic hydrogel with polyvinyl alcohol (PVA) having (8%) gel andwater (92%), cross-linked by freezing/thawing cycles, and can be used incombination with a chemotherapeutic agent and or anti-androgen thephytocannabinoid is preferably CBG or CBD, which may be in the form of aBDS.

In a further embodiment the one or more phytocannabinoids infused in oilor PVA or PVA can be used for the purpose of slowing down the growth orreducing the volume of a prostate cancer tumour.

The use of one or more propyl phytocannabinoids or acidphytocannabinoids infused in oil or synthetic hydrogel with polyvinylalcohol (8%) gel and water (92%), cross-linked by freezing/thawingcycles, and can be for use in the down regulation of ERK signalling andeffect one or more of: anti-proliferation, anti-metastasis oranti-angiogenesis in a human patient.

The use of one or more propyl phytocannabinoids or acidphytocannabinoids infused in oil or PVA in the manufacture of amedicament to down regulate ERK signalling and effect one or more of:anti-proliferation, anti-metastasis or anti-angiogenesis in a humanpatient.

A method of treating a patient with cancer comprising administering oneor more propyl phytocannabinoids or acid phytocannabinoids infused inoil or PVA to down regulate ERK signalling and effect one or more of:anti-proliferation, anti-metastasis or anti-angiogenesis to the patient.

Preferably the one or more phytocannabinoids are selected from the groupconsisting of: THCV, CBGV, CBDV, CBGA and CBDA.

Preferably the one or more phytocannabinoids are in an isolated form.

Preferably the one or more propyl or acid phytocannabinoids infused inoil or PVA are for use in the treatment of lung cancer, prostate cancer,or breast cancer.

Preferably the one or more propyl or acid phytocannabinoids infused inoil or PVA are for use in the treatment of bone or lymph metastasis.

The method includes the use of one or more phytocannabinoid acidsinfused in oil or PVA, excluding CBDA or CBDVA, for use in medicine.

The method includes the use of the one or more phytocannabinoid acidsfor use in the treatment of cancer.

The use of one or more phytocannabinoid acids infused in oil or PVA isdone in the manufacture of a medicament for use in the treatment ofcancer.

The method includes treating a patient with cancer comprisingadministering a therapeutic amount of one or more phytocannabinoid acidsinfused in oil or PVA to the patient. Preferably the one or morephytocannabinoid acids are in the form of a BDS. Preferably the cancerto be treated is a cancer of the prostate, breast, colon, lung, gliomaor skin. Preferably the phytocannabinoid acid is taken from the groupconsisting of: THCA, CBGA and CBDA. More preferably there is provided acombination of the phytocannabinoid THCA with CBDA and/or CBGA.

The method includes applying an isolated CBD, CBG, CBDV, CBD BDS, CBGBDS and/or CBDV BDS infused in oil or PVA for use in the treatment of apre-cancerous symptom of colon cancer.

The method includes infusing in oil an isolated CBD, CBG, CBDV, CBD BDS,CBG BDS and/or CBDV BDS infused in oil or PVA in the manufacture of amedicament to treat a pre-cancerous symptom of colon cancer.

The method of treating a patient with a pre-cancerous symptom of coloncancer, comprising administering a therapeutically effective amount ofan isolated CBD, CBG, CBDV, CBD BDS, CBG BDS and/or CBDV BDS infused inoil or PVA to the patient.

In one embodiment the isolated CBD, CBG, CBDV, CBD BDS, CBG BDS and/orCBDV BDS infused in oil or PVA are used in the treatment of aberrantcrypts in the colon.

In a further embodiment the isolated CBD, CBG, CBDV, CBD BDS, CBG BDSand/or CBDV BDS infused in oil or PVA are used in the treatment of colonpolyps.

A combination of phytocannabinoids infused in oil or PVA together with achemotherapeutic agent which is not a cannabinoid, can be used in thetreatment of a glioma.

A combination of phytocannabinoids infused in oil or PVA together with achemotherapeutic agent which is not a cannabinoid, can be used as amedicament to treat a glioma.

A method of treating a patient with a glioma, includes administering atherapeutically effective amount of a combination of phytocannabinoidsinfused in oil or PVA together with a chemotherapeutic agent which isnot a cannabinoid, to the patient.

Preferably the combination of phytocannabinoids and the chemotherapeuticagent which is not a cannabinoid are packaged for administrationseparately, simultaneously or sequentially. Preferably thephytocannabinoids are THC and CBD. Preferably the dose level of thephytocannabinoids is sub-effective for the treatment of the glioma ifused alone. Preferably the chemotherapeutic agent is temazolamide.Preferably the dose level of the temazolamide is sub-effective for thetreatment of glioma if used alone.

The CBD or TCH can be embedded with a slow release agent.

In one embodiment, a time delay barrier can be used. This outer barrierlayer of a more hydrophobic substance can be selected from polylacticacid (PLA), polyglycolic acid (PGA), a copolymer of PLA and PGA (PLGA),polycaprolactone (PCL), other biodegradable polyesters, polyamino acids,or other hydrophobic, biodegradable polymers.

Preferably, under the barrier layer and immediately adjacent to thecannabis as the therapeutic agent matrix layer another layer is providedthat is instead slightly hydrophilic or closer in polarity to thetherapeutic agent itself than the outer barrier layer. This middle layeris the key to the rapid, burst characteristic of therapeutic agentelution while the outer barrier layer is the key to the delayed onsetcharacteristic of therapeutic agent elution.

As an alternative or as a complement to providing a separate layerbeneath the barrier layer that is opposite in polarity to the barrierlayer and closer in polarity to the therapeutic agent, the material usedto form the therapeutic agent soluble material can be provided inpockets distributed throughout the barrier layer. By interspersing thebarrier matrix with pockets of a hydrophilic substance (i.e. dextran,heparin) a switch effect for accelerated barrier layer degradation andtherapeutic agent elution can be better achieved. Upon a threshold levelof water penetration into the barrier matrix containing the pockets, thepockets increase in pressure to the point where they burst to destroythe barrier structure. The pockets act as isolated reservoirs or oasesfor hydrophilic physiologic and other fluids that the barrier layer'sbase material does not readily accept. Although the biodegradation ofthe barrier layer may be directed by other means such as the emergenceof a restenotic environment in which the barrier layer dissolves, theincorporation of pockets allows additional options for fine-tuning thetiming of barrier degradation by also making it indirectly susceptibleto hydrophilic fluids and environments.

If the therapeutic agent happens to be hydrophobic rather thanhydrophilic the polarities (hydrophobicity and hydrophilicity) of therespective matrices, layers, and/or pockets should be reversed. Thebottom line is that the outermost barrier layer is to be opposite inpolarity to the therapeutic agent and the inner layer(s) or pocket(s)that are closer to the therapeutic agent are closer in polarity to thetherapeutic agent. However, preferably the therapeutic agent itself iscontained in a matrix that is opposite in polarity for stabilization.The design is sandwich-like in configuration with the outer barrier andthe therapeutic agent matrix analogized to pieces of bread between theunique opposite polarity inner layer or pockets analogized to the meat.The inner opposite polarity layer is the trigger to burst elutionbecause the therapeutic agent easily dissolves within it suddenly andcompletely.

Under the event triggered approach, there are several ways to triggerthe switch to allow therapeutic agent elution to occur upon tissueencapsulation of the CBD or TCH:

1. First, the coating covering the therapeutic agent matrix is designedto immediately break down to allow therapeutic agent elution upon tissueencapsulation. This can be achieved by coating the therapeutic agentmatrix with a slightly to hydrophobic, biodegradable outer barrier layerthat breaks down quickly upon the presence of a slightly to veryhydrophobic environment such as provided by restenotic material. A thinlayer of wax or a fatty substance exemplify the type of coating to beused. Specific examples of these include lipoprotein, collagen,polyamino acids, PLA, PLGA, and polycaprolactone,

2. Second, the ECM suppressing therapeutic agent can be bound to amolecule that inactivates the therapeutic agent until ECM factors (i.e.collagen, proteoglycans) are present.

3. Third, the switch can be turned on by other factors accompanyingtissue encapsulation or extracellular matrix thickening including:hormones, enzymes, and/or peptides, etc.

4. Fourth, pressure can be used to induce release of the therapeuticagent, i.e. by housing the therapeutic agent within a semi-permeablemembrane that bursts or by including pressure-building pockets within abarrier layer.

5. Fifth, pH changes can be used to induce release of the therapeuticagent if the material retaining (i.e. coating or serving as a matrixfor) the therapeutic agent is sensitive to acids or bases and degrades(in tissue or in blood) upon being subjected to acidic or basicenvironments. In one embodiment, the therapeutic agent is coated with aslightly hydrophobic, acid-sensitive layer of PLGA. Tissue encapsulationof the CBD or TCH can trap the PLGA and the acids produced from PLGAdegradation. Subsequently, the concentration of acids is dramaticallyincreased which leads to rapid degradation of the PLGA itself.

This event triggered approach offers a high degree of control oftherapeutic agent elution and/or activation. The onset of therapeuticagent elution and/or the catalyst for therapeutic agent activation isparticularized to occur independently and exclusively on the CBD or TCHlocalities encapsulated by tissue while the elution is restrained and/orthe therapeutic agent remains dormant and inactive on the CBD or TCHlocalities that are still bare and un-encapsulated. Encapsulation ratesvary between procedures, individuals, and CBD or TCH localities.Therefore, event-triggered therapeutic agent control provides anindividualized approach for enhanced accuracy, safety and effectiveness.

It is preferred that the dosage of the anti-restenosis therapeutic agentis higher at the ends of the CBD or TCH to compensate more aggressiverestenosis at the ends of the CBD or TCH.

In one embodiment, the present invention uses aligned nanofibers and/oraligned nanogrooves to form the CBD or TCH coating to create anartificial functional endothelial layer that will attract the depositionof a natural endothelial layer. The natural endothelial layer iscomposed of aligned, elongated endothelial cells that will alignthemselves amongst the aligned fibers and deposit directly on the CBD orTCH itself even when the aligned nanofiber coating is not loaded withany specifically reactive linking agents.

The xenographic/xenogenic artificial functional endothelial layer ofaligned fibers and/or aligned grooves may be composed of or seeded withsynthetic materials, allogeneic materials (cells or clones from a secondsubject of the same species as the patient), and/or heterologousmaterials (cells or clones from a second subject not of the same speciesas the patient). In any case, the aligned geometry of the artificialfunctional layer paves the way for the growth of a natural functionallayer of autologous endothelial cells produced in vivo that willencapsulate the CBD or TCH CBD or TCHs and injured to tissue to a depthof 0.1 mm thereby masking its xenographic (foreign) nature to precludean immune response that may cause thrombosis.

One embodiment addresses LST without sacrificing the effectiveness ofusing restenosis suppressing therapeutic agents to avoid late stagerestenosis and using ECM regulating therapeutic agents to reducethickening of the ECM. This is done by depositing a biodegradable layerof aligned microfibers (AMF), aligned nanofibers (ANF), and/or alignedgrooves (AG) on top of a DES as an effective means to delay the onset ofrelease of one or more therapeutic agent (i.e. restenosis or ECMinhibitory therapeutic agents) as well as to facilitate endothelization(see FIG. 2 and FIG. 3). This way the patient benefits from two desiredcharacteristics:

1. the safety of the BMS by having a smooth endothelium or neointimaencapsulating the CBD or TCH CBD or TCHs; and

2. the long term effectiveness of proven DES (such as Cypher and Taxus)by maintaining delivery of a local restenosis and/or ECM suppressingtherapeutic agent from the CBD or TCH but with a delayed onset.

The AMF/ANF/AG material may take the form of a coating, a matrix, or anCBD or TCH body so long as its structure and orientation are such thatit can both facilitate endothelization and also delay the onset oftherapeutic agent release, if therapeutic agents are used. Preferably,the AMF/ANF/AG material lasts for 15-30 days before it is fully degradedto expose the therapeutic agent underneath. However, it may work byfully degrading anywhere between 5-60 days. The AMF/ANF/AG material ispreferably made of PGA or a copolymer of PGA-PLA. These are provencompounds used on DES as well as biodegradable sutures and are welldocumented for their compatibility with blood. PGA and PGA-PLA areespecially well suited to degrade within 15-30 days. The delay timebefore onset of release of the ECM suppressing therapeutic agent (i.e.fluoroquinolone, glucosamine, diethylcarbamazine, etc.) is equal to thetime it takes the AMF/ANF/AG material to fully degrade. This delay timeis controlled by the exact chemical compounds used to create the coatingand also the coating thickness. For example, since 50% PLA:50% PGAdegrades more quickly than a 75% PLA:25% PGA mix, to obtain the sametherapeutic agent release onset delay a thicker layer of 50% PLA:50% PGAwould be used than if a 75% PLA:25% PGA mix were used. The AMF/ANF/AGmaterial is preferably between 0.1 micron and 20 microns thick.

Alternatively, instead of PGA and/or PLA, the AMF/ANF/AG material canalso preferably be made of poly(ethylene glycol) (PEG), also known aspoly(ethylene oxide) (PEO) or polyoxyethylene (POE). Caprolactone (CPL)can also be used. CPL and PEG are elastomeric materials and if theAMF/ANF/AG medical device has elastomeric properties it will betterconform to the natural shape of the lumen in which it is inserted or CBDor TCHed. Elastomeric materials are better able to close gaps between aCBD or TCH wall and a lumen wall. Avoiding incomplete apposition of theCBD or TCH CBD or TCHs against the lumen wall reduces the formation ofstagnant pockets in which a thrombus is more likely to develop. MetallicCBD or TCH CBD or TCHs are typically stiff and cannot conform well tothe lumen when the lumen is not smooth and uniform, as is often thecase. However, an elastomeric coating upon non-elastomeric CBD or TCHCBD or TCHs ameliorates this problem by flexing, bending, expanding, andcontracting to occupy the differential spaces created by thenonconformity between the lumen wall and the CBD or TCH CBD or TCHs.Alternatively, if the CBD or TCH CBD or TCHs themselves are made ofAMF/ANF/AG elastomeric materials they can directly model the irregularsurface patterns of anatomic lumens.

The AMF/ANF/AG material can also be made out of biological molecules(biomolecules) such as collagen, fibrin, or fibrinogen. Various othersubstances that can be used to form the AMF/ANF/AG material are:phosphorylcholine, nitric oxide, high density lipoprotein, polyzene-F,PTFE polyetherester, hydroxyapatite, polyhydroxy-butyrate,polycaprolactone, polyanhydride, poly-ortho ester, polyiminocarbonates,polyamino acids, and polyvinyl alcohol.

Irrespective of the chemical components used to form the AMF/ANF/AGmaterial, when used as a delay coating the AMF/ANF/AG material ispreferably negatively charged and also preferably has a nitric oxidefunctional group. Thus, as the fibers degrade, nitric oxide is released.Within the bloodstream of the lumen occupied by the CBD or TCH, thenitric oxide serves to further inhibit restenosis by preventing plateletaggregation and macrophage/leukocyte infiltration, reducing smoothmuscle cell proliferation, and decreasing inflammation generally whileaiding the healing process. An aligned coating with a nitric oxide group(ANO) on an CBD or TCH (or other intravascular medical device) forms anartificial endothelium layer due to the smooth, streamlined surface thealigned fibers/grooves provide coupled with the ability of nitric oxideto prevent aberrations on this smooth surface as the fibers degrade.

The inventor recognizes the use of any biocompatible materials that canbe formed into aligned nanofibers, aligned microfibers, or alignedgrooves for the AMF/ANF/AG material used to form an CBD or TCH, acoating, or a matrix for therapeutic agent(s). The present inventionalso recognizes the ability to use the AMF/ANF/AG material inconjunction with other coatings, layers, matrices, pores, channels,reservoirs, etc. to delay onset of the release of any therapeutic agentand/or to encourage structured (i.e. aligned) endothelization.

The present invention also teaches the criticality of matching the timeperiod of delay prior to therapeutic agent release with the time ittakes for the AMF/ANF/AG CBD or TCH surface to become covered (i.e.encapsulated) by endothelization to a depth of approximately 0.1 mm. Theartificial functional endothelium layer itself is a very thin (i.e. onlyone or a few cells thick). A thin layer does not burden the CBD or TCHwith unnecessary volume (i.e. on the periphery of a cross-section) thatcould make insertion and adjustment within the lumen more difficult. Athin layer also does not significantly reduce the inner diameter of theCBD or TCH's lumen and therefore does not interfere with hemodynamics orobstruct blood supply to a treated area.

When the CBD or TCH is not formed of a material (i.e. such as anelastomeric aligned material) that enables it to conform to the shape ofa lumen surface, a thrombus is more likely to develop causing alocalized inflammatory reaction. Also, when the CBD or TCH doesn'tconform well to the shape of a lumen, the process of restenosis cannotbe effectively controlled. Although systematic therapeutic agentsadministered with BMS and therapeutic agents supplied by DES can slow ormodulate the rate of ineffective restenosis they are not typically usedto encourage a moderate amount of beneficial restenosis. Any restenosisthat does occur in a vessel having an uneven surface with CBD or TCH CBDor TCHs that inadequately conform to the natural cell and proteinstructure (and/or shape) of the vessel is likely to be uncontrollableand problematic. Smooth muscle cell migration and proliferation islikely to form the first tissue layer over the CBD or TCH CBD or TCHs.In contrast, the present invention provides a pre-formed artificialfunctional endothelial layer to provoke a first in vivo layer of naturalendothelial cell growth.

According to the present invention, an aligned (i.e. AMF/ANF/AG/ANO)coating on the luminal surface aligns both the blood flow and the growthof natural endothelial cell layers in a uniform, optimal direction (i.e.longitudinally along the central axis of the lumen). An aligned innercoating accelerates and optimizes blood flow for better drainage andsupport. Normal blood flow around the CBD or TCH flushes out immuneresponse agents and toxins, as they are produced, to accelerate drainageand healing. Normal blood flow also feeds the developing, naturalendothelial cell layer above the artificial functional endothelial CBDor TCH coating with nutrients.

Once the natural endothelial cell layer has developed to a sufficientextent (i.e. a depth of approximately 0.1 mm) and moderate amounts ofbeneficial (i.e. aligned) restenosis have been permitted to occur, theresult is a camouflaged CBD or TCH buried within normal, healthy tissue.No foreign materials are detectable by the blood and so the bloodrelated immune response and inflammation are inhibited, thereby greatlyreducing the risk of thrombosis. As therapeutic agents begin to beeluted from DES upon degradation of the aligned coating, the beneficial,controlled restenosis process (“encapsulation”) comes to a halt. The CBDor TCH remains stably buried but the thickness of the luminal wallsstops increasing to avoid reclosure. The therapeutic agents are powerfulenough to prevent additional encapsulation but cannot undo thebeneficial, CBD or TCH-sealing, encapsulation that has already occurred.

Elution of the therapeutic ECM suppressing therapeutic agent will arrestthe proliferation of neointima (protein deposition) (see FIG. 4). Due tothe delay in the onset of therapeutic agent release, by the time thetherapeutic agents are released all the CBD or TCH CBD or TCHs areencapsulated with endothelium and/or smooth muscle. Therefore, higherdosages of therapeutic agents, faster elution rates, and/or moreaggressive therapeutic agents can be used to ensure maximumeffectiveness in preventing restenosis and inhibiting excessive ECMthickening in the long term without fear of LST from an immune reaction.Once the CBD or TCH CBD or TCHs are smoothly buried beneath a thinnatural tissue layer thrombosis is unlikely.

Optionally, the CBD or TCH may have semi-permeable cross-sectional sidewalls extending through the surface area of the cross section on eachend adjacent to a target site to be treated with an eluted therapeuticagent. The side walls would serve as barriers to the therapeutic agentto concentrate it at the target site and avoid the negative effects ofsystematic therapeutic agent distribution. Such sidewalls would alsoconserve the therapeutic agent to be maintained where it is needed mostto allow less total therapeutic agent within the CBD or TCH to beequally effective by reducing the washout effect. Reducing the totaltherapeutic agent stored in the state (while maintaining effectiveness)is beneficial because then the CBD or TCH walls can be thinner and it isalso less expensive. The semi-permeable nature of the side walls allowsthem to permit the influx of important nutrients needed at theconstricted vessel site and to permit the out flux of waste thuspreserving hemodynamics. The cross-sectional side walls would dissolvenaturally in time to correspond with the termination of the desiredtherapeutic agent treatment period.

Optionally, the CBD or TCH may include radio-opaque substances in one ormore of the materials of which it is formed or in one or more coatings.An array of different, distinguishable radio-opaque substances may alsobe used in each layer or coating. These substances would enable aphysician to externally observe the placement, progress, and improvementof the CBD or TCHing procedure without causing the patient discomfortfrom an internal inspection and without risking displacing the CBD orTCH during an internal (i.e. endoscopic) inspection.

Another approach to avoiding LST while still controlling restenosis isby accelerating the endothelization of the CBD or TCH through alignedscaffolding without the antirestenosis therapeutic agent. The bare CBDor TCH can be made of (at least in part) or coated with elongatedAMF/ANF/AG/ANO aligned with the direction of blood flow (i.e. long axisof fibers parallel to the direction of blood flow). Endothelial cells(ECs) are themselves elongated and tend to also be aligned with thedirection of blood flow. By aligning the fibers with the preferredalignment of ECs, the deposition of ECs over the CBD or TCH (includingbut not limited to the CBD or TCH CBD or TCHs) is accelerated (alignedscaffolding). The presence of ECs tends to arrest the restenosis process(smooth muscle proliferation). The AMF/ANF/AG/ANO are preferably laiddown on the inner diameter (ID) of the CBD or TCH (see FIG. 3). Theouter diameter (OD) or abluminal surface of the CBD or TCH is typicallyembedded in or aligned against the luminal surface of the vessel so thatthe longitudinal alignment of the fibers here is not as important as forthe inner diameter or luminal surface of the CBD or TCH.

The CBD or TCH CBD or TCHs are typically 50 to 100 microns wide. Thefibers are preferably 0.5 to 10 microns wide. Therefore, regardless ofthe CBD or TCH CBD or TCH orientation, the fibers can have an aspectratio of 5 or greater. By having an aspect ratio greater than 2, thefibers can provide effective longitudinally aligned scaffolding for ECsto grow on.

The AMF/ANF/AG/ANO coating or surface can be impregnated or coated withantiplatelet or anticoagulant therapeutic agents such as heparin,ticlopidine, chlopidrel, enoxaparin, dalteparin, hirudin, dextran,bivalirudin, argatroban, danparoid, Tissue Factor Pathway Inhibitor(TFPI), GPVI antagonists, antagonists to the platelet adhesion receptor(GP1b-V-IX), antagonists to the platelet aggregation receptor(GPIIb-IIIa) or any combination of the aforementioned agents.

The AMF/ANF/AG/ANO material can also be impregnated with endothelizationpromoting substances such as vascular endothelial growth factor (VEGF),angiopoietin-1, antibodies to CD34 receptors, and/or hirudin, dextran.

The coating can be applied to the inner diameter (ID) of the CBD or TCHin the form of longitudinally aligned microfibers, nanofibers, grooves,or nitric oxide carrying elements by several modified processes ofelectrospinning:

1A. Aligned Nanofibers on CBD or TCH CBD or TCHs only: A dispensingsyringe is loaded with a solution of the fiber material and is charged(i.e. positive) with a high voltage (>1 kV) to charge the solution. TheCBD or TCH is either grounded or charged by applying the oppositevoltage (i.e. negative). The outer diameter (OD) of the CBD or TCH iscovered with a polar or conductive tube that sticks to the fibermaterial well. For example, if PGA or PLA are used as the polymersolution from which the fiber material is formed, polyethyleneterephthalate (PET) is heat shrunk on the OD of the CBD or TCH. The CBDor TCH is held by a grounded or charged (i.e. negative) collet on the ODof one end. The dispensing syringe needle with a 90 degrees bend (orside hole) at the tip is inserted inside the ID of the CBD or TCH fromthe open end of the CBD or TCH. The charged solution is dispensed fromthe needle tip onto the CBD or TCH ID as longitudinally alignedmicro/nanofibers/grooves/nitric-oxide carrying elements as the syringetip is moved back and forth longitudinally. As the syringe tip completesone pass from one end to the other, the collet is indexed (turnedincrementally) to lay down the adjacent fiber. This process continuesuntil the whole CBD or TCH ID is covered with aligned fibers, grooves orelements. Once the coating is finished, the cover (i.e. polar orconductive tube such as PET) on the OD can be peeled off to clear theCBD or TCH openings of fibers.

1B. Aligned Nanofibers covering all CBD or TCH: A dispensing syringe isloaded with a solution of the fiber material and is charged (i.e.positive) with a high voltage (>1 kV) to charge the solution. The CBD orTCH is either grounded or charged by applying the opposite voltage (i.e.negative). The CBD or TCH is held by a grounded or charged (i.e.negative) collet on the OD of one end. The dispensing syringe needlewith a 90 degrees bend (or side hole) at the tip is inserted inside theID of the CBD or TCH from the open end of the CBD or TCH. The chargedsolution is dispensed from the needle tip onto the CBD or TCH ID aslongitudinally aligned micro/nanofibers/grooves/nitric-oxide carryingelements as the syringe tip is moved back and forth longitudinally. Asthe syringe tip completes one pass from one end to the other, the colletis indexed (turned incrementally) to lay down the adjacent fiber. Thisprocess continues until the whole CBD or TCH ID is covered with alignedfibers, grooves or elements.

2. The highly charged (i.e. +10 kV) syringe as described above is fixedlongitudinally. The CBD or TCH is grounded. A ring of opposite charge(i.e. −10 kV) is placed near the CBD or TCH. The dispensing syringe ispulsed by pulsing syringe pressure, a needle valve, or charging tocompletely dispense one aligned fiber. The CBD or TCH is thenrotationally indexed for the next pulsed dispensing.

3. A hollow ring containing the solution of fiber material has series ofmicro/nano-holes on the end for dispensing parallel fibers arranged in adiameter close to the diameter of the CBD or TCH. The ring is highlycharged (i.e. +10 kV) to charge the fiber material in solution. The CBDor TCH is grounded. A ring close to the diameter of the CBD or TCH ischarged with an opposite charge (i.e. −10 kV) on the opposite end of theCBD or TCH. This charged state will cause the solution which forms thefibers to eject from the holes in parallel, longitudinally towards theoppositely charged ring while simultaneously adhering to the CBD or TCHalong the path from one ring to another.

In another embodiment, the inner surface of the CBD or TCH CBD or TCHcan have micro/nano-grooves etched on it longitudinally (parallel toaxis of CBD or TCH). ECs will tend to grow into these grooves. Thegrooves are preferably 1 to 10 microns wide. In the same manner, thegrooves can also be ridges or channels. The longitudinally alignedmicro/nano-grooves may also be used as reservoirs or longitudinal wellsfor storing therapeutic agents within the aligned fiber layers forcontrolled or multi-phase elution.

These AMF/ANF/AG/ANO CBD or TCHs are particularly advantageous whenapplied to intravascular bifurcations or vessels with one or morecorollary branch adjacent to a main lumen. Bifurcated vessels tend tohave much higher rates of restenosis with both conventional BMS and DESthan do non-bifurcated vessels.

The present invention controls tissue encapsulation of the CBD or TCHand of injured tissue in at least three ways: biologically,geometrically, and chronologically.

Biologically, aligned nano/microfibers with or without alignednano/microgrooves therein (or alternatively, aligned grooves formedwithin a non-fibrous material) facilitate functional endothelization byencouraging a uniform orientation in any cell growth that occurs(whether of true endothelial cells or artificial endothelial cells). Thepolymers or other materials chosen for the construction of thenano/microfibers or nano/microgrooves must be biocompatible to permitthe natural flow of blood and other bodily fluids through the lumenadjacent the CBD or TCH's inner surface without elicitation of an immuneresponse or thrombosis. The materials used to form the fibers or thematerial within which the grooves are etched can be synthetic ornaturally derived. Suitable materials include: biodegradable materialssuch as polyglycolic acid (PGA), polylactic acid (PLA), copolymer of PLAand PGA (PLGA), hydroxyapatite (HA), polyetherester,polyhydroxybutyrate, polyvalerate, polycaprolactone, polyanhydride,poly-ortho ester, polyiminocarbonates, polyamino acids, polyethyleneglycol, polyethylene oxide, and polyvinyl alcohol; non-biodegradablepolymers such as fluoropolymer like Polytetrafluoroethylene (PTFE),polyzene-F, polycarbonate, carbon fiber, nylon, polyimide, Polyetherether ketone, polymethylmethacrylate, polybutylmethacrylate,polyethylene, polyolefin, silicone, and polyester; biological substancessuch as high density lipoprotein, collagen, fibrin, phosphorylcholine(PC), gelatin, dextran, or fibrinogen.

Geometrically, the invention is designed to only allow 0.1 mm thicknessof encapsulation (of CBD or TCH CBD or TCHs or the entire CBD or TCHbody and of injured tissue) before the therapeutic agent elution processbegins to inhibit further encapsulation. Another aspect of geometriccontrol is the alignment of fibers/grooves and all growth thereuponwhether it be endothelial cells, smooth muscle cells, proteins, matrixfibers, or collagen fibers. Due to the structure supplied by thefibers/grooves, all subsequent in vivo growth, migration, and/orproliferation is necessarily aligned to correspond to the template setby the fibers/grooves. Aligned growth does not interfere with bloodflow. Further, even if the initial natural layers of biologicallyderived materials deposited are not the ideal materials (i.e. smoothmuscle cells instead of endothelial cells), as long as they are alignedthey are suspected not to impede the deposition of the optimal materialswhen they come along.

Chronologically, the invention assures that the complete degradation ofthe polymer (or other material) layer serving as a delay coat for theantiproliferative therapeutic agent corresponds to the time when anoptimal amount (i.e. 0.1 mm thickness) of encapsulation has occurredbecause that point in time also marks the onset of elution of theantiproliferative therapeutic agent which will suppress furtherthickening of tissue encapsulation. Temporal control over the elution ofthe antiproliferative and/or other therapeutic agents may also beachieved by an external activation means that signals for the alignedtherapeutic agent reservoirs to begin elution. The external activationmeans may be electromagnetic radiation, infrared light, microwaveradiation, x-ray radiation, etc. This type of external activation meanswould provide very precise control of the onset of therapeutic agentelution. Since the rate of encapsulation will vary from individual toindividual and from procedure to procedure depending upon a multitude offactors, a pre-elution assessment (i.e. imaging for endothelial cellmarkers) of the extent of encapsulation can precede initiation of theexternal activation means to ensure elution does not begin prematurely.

In some embodiments, the teachings are directed to a therapeutic coatingthat promotes formation of a functional endothelium on a medical device.In these embodiments, the coating comprises a biodegradabledrug-containing layer that is positioned over a surface of a medicaldevice and serves as a source of a drug that functions as ananti-proliferative agent in a subject. The coating also comprises abiodegradable drug-reservoir layer positioned over a surface of thedrug-containing layer. The drug-reservoir layer comprises adrug-retaining layer, wherein the drug-retaining layer is void orsubstantially void of the drug at a time of implantation in the subjectand functions to retain and at least substantially block an initialrelease of the drug into the subject for a time sufficient to form afunctional endothelium over the surface of the medical device. In theseembodiments, the functional endothelium can provide a source ofthrombomodulin to the subject. It should be appreciated that the drugmay be at least substantially miscible in the drug-reservoir layer tofacilitate a retention of the drug. It should be appreciated that thetime sufficient to form a functional endothelium may vary according toselection of subject, medical device, location of an CBD or TCH,materials used, and the like. In some embodiments, the time can be atleast about 20 days.

In some embodiments, the drug-containing layer can comprise apoly(lactic-co-glycolic acid), a monomer ratio of lactic acid toglycolic acid ranges from about 85:15 to about 50:50, and a molecularweight ranging from about 90 KDaltons to about 160 KDaltons. And, insome embodiments, the drug-retaining layer can comprise apoly(lactic-co-glycolic acid) having ester terminal groups, a monomerratio of lactic acid to glycolic acid ranging from about 85:15 to about50:50, and a molecular weight ranging from about 90 KDaltons to about160 KDaltons.

Moreover, the drug-retaining layer can comprise a polymer havingester-terminal groups. The polymer can have, for example, a molecularweight ranging from about 50 KDaltons to about 190 KDaltons, and astructure that remains at least substantially undegraded during theinitial release of the drug, the structure comprising P—CO2R, where P isthe polymer backbone and R is an alkyl group having from 1 to 4 carbons.

The coating may at least substantially promote development of thefunctional endothelium as the source of the thrombomodulin when comparedto a control development of such endothelium formation observedfollowing CBD or TCHation of a metal or polymer drug-eluting medicaldevice. In addition, the coating may at least substantially inhibitdevelopment of a hyperproliferative tissue when compared to a controldevelopment of such hyperproliferative tissue observed following CBD orTCHation of a metal or polymer medical device that does not elute adrug. In some embodiments, the medical device comprises a CBD or TCH.

The coatings can be designed for a delay time before onset of therelease of the drug and elution of the drug at a certain rate. In someembodiments, the drug-reservoir layer can further comprise an accelerantlayer to accelerate the onset of elution. And, in some embodiments, theaccelerant layer having a poly(lactic-co-glycolic acid) with acidterminal groups, a monomer ratio of lactic acid to glycolic acid thatranges from about 85:15 to about 50:50, and a molecular weight thatranges from about 90 KDaltons to about 120 KDaltons. In someembodiments, the accelerant layer can comprise a drug. The amount ofdrug in the accelerant layer can be 0, 5, 10, 15, 20, 25, 30, 35, 40,45, 50, 60 percent, or any amount therein.

In fact, other variables can be used to design for a desired delay timeand release rate of the drug. In some embodiments, for example, thethickness ratio of the drug-reservoir layer to the drug-containing layercan range from about 4:1 to about 10:1, and the miscibility of the drugin a coating can be preselected to affect the rate of drug migration. Insome embodiments, the thickness of the coating can range from about 2microns to about 9 microns. And, in some embodiments, the thicknessratio of the drug-retaining layer to the drug-containing layer rangesfrom about 4:1 to about 7:1.

As such, the teachings are generally directed to a method of inhibitingthe formation of hyperproliferative tissue and promoting the formationof a functional endothelium after implantation of a medical device in asubject. The method can comprise applying a therapeutic coating on amedical device and CBD or TCHing the device in the subject. In someembodiments, the coating can comprise a biodegradable drug-containinglayer that (i) is positioned over a surface of a medical device and (ii)serves as a source of a drug that functions as an anti-proliferativeagent in a subject; and, a biodegradable drug-reservoir layer positionedover a surface of the drug-containing layer and comprising adrug-retaining layer, the drug-retaining layer remaining void orsubstantially void of the drug at a time of implantation in the subjectand functioning to retain and at least substantially block an initialrelease of the drug into the subject for a time sufficient to form afunctional endothelium over the surface of the medical device, thefunctional endothelium providing a source of thrombomodulin to thesubject.

In some embodiments, the drug-containing layer can be applied as asolvent mixture and the solvent can be dried after application using asubstantially non-reactive heated gas. The drying can serve to at leastsubstantially inhibit mobilization of the drug from the drug-containinglayer during application of additional layers in the formation of thecoating. In some embodiments, the drug-reservoir layer can comprise atleast one sub-layer having a thickness of less than or equal to 3microns, where a repeated application of the sub-layer can be used toform thicknesses of greater than 3 microns. In some embodiments, theaccelerant layer can be positioned between the drug-containing layer andthe remainder of the drug-reservoir layer, is more hydrophilic than theremainder of the drug-reservoir layer, and comprises at least onesub-layer having a thickness of less than or equal to 3 microns, where arepeated application the sub-layer is used to form thicknesses ofgreater than 3 microns. The application of the sub-layers can be used toat least substantially promote a retention of the drug in thedrug-containing layer during formation of the coating when compared tosuch a coating without the application of the sub-layers.

The coatings taught herein can, in some embodiments, further comprisepockets of hydrophilic material in the drug-retaining layer, wherein thehydrophilic material comprises a component selected from the groupconsisting of dextran, heparin, ticlopidine, chlopidogrel, enoxaparin,dalteparin, hirudin, bivalirudin, argatroban, and danparoid. And, insome embodiments, the drug can be selected from the group consisting offluoroquinolone, paclitaxel, rapamycin, sirolimus, everolimus, biolimus,zotarolimus, tacrolimus, fibroblast growth factor (bFGF), rapamycinanalogs, antisense dexamethasone, angiopeptin, BATIMISTAT, tranilast,transilast, halofuginon, acetylsalicylic acid, hirudin, steroids,ibuprofen, antimicrobials, antibiotics, actinomycin D, tissue plasmaactivators, estradiol, and transcription factor E2F1.

It should be appreciated that, in the embodiments taught herein, thedrug may be selected by its miscibility in a preselected polymer matrix.For example, the drug may be selected because it is at leastsubstantially miscible in the drug-reservoir layer in order to retainthe drug for a desired amount of time. Or, the drug may be miscible to apreselected degree, an amount sufficient to facilitate a desiredretention time of the drug. A desired retention time is facilitated, forexample, in a case where a functional endothelium has formed to adesired extent. It should be appreciated that the desired retention timeis facilitated where the retention time is modulated to a desiredamount, and the modulation of the time can include an increase or adecrease in the retention time through altering one or more coatingvariables, as described herein. One of skill should appreciate, forexample, that miscibility of the drug with the polymer is a variablethat can modulate an affinity of the drug for the polymer, in someembodiments, thus affecting retention time.

In some embodiments, the drug and polymer are mixed or blended insolution, and one skill will appreciate that the mixes or blends can beconsidered substantially miscible, for example, where they mix or blendhomogeneously in the desired proportions of drug to polymer, at leastfor the purposes of the teachings provided herein. In contrast, themixes or blends may be considered immiscible, at least for the purposesof the teachings provided herein, where the mix or blend of polymer anddrug is not homogeneous in the mix or blend in the proportions desired.In some embodiments, a drug can be considered substantially miscible ina polymer, where a homogeneous, saturated solution comprising the drugin a solvent spreads on a layer of the polymer, such that (i) thesolution of the drug in the solvent has a contact angle of greater than90 degrees on the surface of the polymer; and (ii) the layer of thepolymer was formed used the same solvent. In some embodiments, the drugis substantially miscible in the polymer where the surface tension ofthe drug and the surface tension of the polymer are the same or similarwhen compared using the same solvent. A surface tension is the same,where the difference is not statistically significant, and similar,where the surface tension does not vary by more than 1, 2, 3, 4, 5, 10,15, 20, 25, or 30 percent, in some embodiments. It should beappreciated, however, that any method known to one of skill can be usedto determine the relative degree of miscibility and affinity between thedrug and the polymer.

In some embodiments, the retention time of a drug can be a timesufficient amount, or an otherwise desired amount of time, chosen basedon any number of parameters recognized and known to one of skill in theart of drug elution from CBD or TCHed medical devices. Such parameterscan vary the desired amount of time based on, for example, type of CBDor TCH, location of CBD or TCH, construction of CBD or TCH, selection ofdrug, desired effect, and the like.

It should be appreciated that the “time sufficient to form a functionalendothelium” may vary according to selection of subject, medical device,location of a CBD or TCH, materials used, and the like. In someembodiments, the time can be at least about 20 days. In someembodiments, a sufficient amount of time can range from about 5 days toabout 120 days, from about 10 days to about 90 days, from about 12 daysto about 50 days, from about 14 days to about 45 days, from about 15days to about 90 days, from about 20 days to about 60 days from about 25days to about 45 days, from about 20 days to about 40 days, from about20 days to about 30 days, from about 25 days to about 35 days, or anyrange therein.

The polymeric compositions taught herein include any desired polymer,combination of polymers, copolymers and agents known to one of skill tobe useful as a medical device, or coating, as taught herein. Thesepolymers can be biodegradable due to their labile nature, such as thelabile nature of the ester groups that are present in some polymers. Insome embodiments, these compositions can be designed such that they canbe broken down, absorbed, resorbed and eliminated by a mammal. As such,the compositions can be used, for example, to form medical articles andcoatings.

The terms “combine,” “combined,” and “combining” all refer to arelationship between components of a composition and include blends,mixtures, linkages, and combinations thereof, of components that formthe compositions. The linkages can be connections that are physical,chemical, or a combination thereof. Examples of physical connectionsinclude, but are not limited to, an interlinking of components that canoccur, for example, in interpenetrating networks and chain entanglement.Examples of chemical connections include, but are not limited to,covalent and noncovalent bonds. Covalent bonds include, but are notlimited to, simple covalent bonds and coordinate bonds. Non-covalentbonds include, but are not limited to, ionic bonds, and inter-molecularattractions such as, for example, hydrogen bonds and attractions createdby induced and permanent dipole-dipole interactions.

Compositions that are selected for an in vivo use should meet particularrequirements with regard to physical, mechanical, chemical, andbiological properties of the compositions. An example of a physicalproperty that can affect the performance of a biodegradable compositionin vivo is water uptake. An example of a mechanical property that canaffect the performance of a composition in vivo is the ability of thecomposition to withstand stresses that can cause mechanical failure ofthe composition such as, for example, cracking, flaking, peeling, andfracturing. An example of a chemical property that can affectperformance of a biodegradable composition in vivo is the rate ofabsorption of the composition by a subject. An example of a biologicalproperty that can affect performance of a composition in vivo is thebioactive and/or bio beneficial nature of the composition,

While not intending to be bound by any theory or mechanism of action,water uptake by a composition can be an important characteristic in thedesign of a composition. Water can act as a plasticizer for modifyingthe mechanical properties of the composition. Control of water uptakecan also provide some control over the hydrolysis of a coating and thuscan provide control over the degradation rate, absorption rate, and theagent release rate of a medical article or coating in vivo, such as forthe release of a drug. In some embodiments, an increase in hydrolysiscan also increase the release rate of an agent by creating channelswithin a medical article or coating that can serve as transport pathwaysfor diffusion of the agents from the composition. The terms “subject”and “patient” can be used interchangeably and refer to an animal such asa mammal including, but not limited to, non-primates such as, forexample, a cow, pig, horse, cat, dog, rat, and mouse; and primates suchas, for example, a monkey, or a human.

In some embodiments, the compositions may be used, for example, to formmedical articles and coatings (i) that have sufficient mechanicalproperties for applications that can benefit from biodegradablepolymers, (ii) that can release agents substantially free of additionalmolecules derived from a polymeric carrier, (iii) that can be designedto have a predetermined release rate and absorption rate; and (iv) thatcan be combined with agents that are not only bioactive and/or biobeneficial but also control a physical property and/or a mechanicalproperty of a medical article or coating formed from the polymer.

A polymer or coating can be “biodegradable,” for example, when it iscapable of being completely or substantially degraded or eroded whenexposed to an in vivo environment or a representative in vitroenvironment. A polymer or coating is capable of being degraded or erodedwhen it can be gradually broken-down, resorbed, absorbed and/oreliminated by, for example, hydrolysis, enzymolysis, oxidation,metabolic processes, bulk or surface erosion, and the like within asubject. It should be appreciated that traces or residue of polymer mayremain on the device, near the site of the device, or near the site of abiodegradable device, following biodegradation. The terms“bioabsorbable” and “biodegradable” are used interchangeably in thisapplication. The polymers used in the teachings herein may bebiodegradable and may include, but are not limited to, condensationcopolymers. In some embodiments, the drug-containing layer can comprisea poly(lactic-co-glycolic acid), a monomer ratio of lactic acid toglycolic acid ranges from about 85:15 to about 50:50, and a molecularweight ranging from about 90 KDaltons to about 160 KDaltons.

Biodegradable polymers can be used, and biodegradable polymers should beselected according to their behavior and hydrolysis in vivo. In someembodiments, the number average molecular weight of the polymerfragments should be at or below about 40,000 Daltons, or any rangetherein. In some embodiments, the molecular weight of the fragmentsrange from about 300 Daltons to about 40,000 Daltons, from about 8,000Daltons to about 30,000 Daltons, from about 10,000 Daltons to about20,000 Daltons, or any range therein. The molecular weights are taughtherein as a number average molecular weight.

Examples of polymers that can be used in some embodiments include, butare not limited to, poly(acrylates) such as poly(butyl methacrylate),poly(ethyl methacrylate), poly(hydroxylethyl methacrylate), poly(ethylmethacrylate-co-butyl methacrylate), copolymers of ethylene-methylmethacrylate; poly(2-acrylamido-2-methylpropane sulfonic acid), andpolymers and copolymers of aminopropyl methacrylamide;poly(cyanoacrylates); poly(carboxylic acids); poly(vinyl alcohols);poly(maleic anhydride) and copolymers of maleic anhydride; fluorinatedpolymers or copolymers such as poly(vinylidene fluoride),poly(vinylidene fluoride-co-hexafluoro propene),poly(tetrafluoroethylene), and expanded poly(tetrafluoroethylene);poly(sulfone); poly(N-vinyl pyrrolidone); poly(aminocarbonates);poly(iminocarbonates); poly(anhydride-co-imides), poly(hydroxyvalerate);poly(L-lactic acid); poly(L-lactide); poly(caprolactones);poly(lactide-co-glycolide); poly(hydroxybutyrates);poly(hydroxybutyrate-co-valerate); poly(dioxanones); poly(orthoesters);poly(anhydrides); poly(glycolic acid); poly(glycolide); poly(D,L-lacticacid); poly(D,L-lactide); poly(glycolic acid-co-trimethylene carbonate);poly(phosphoesters); poly(phosphoester urethane); poly(trimethylenecarbonate); poly(iminocarbonate); poly(ethylene); poly(propylene)co-poly(ether-esters) such as, for example, poly(dioxanone) andpoly(ethylene oxide)/poly(lactic acid); poly(anhydrides), poly(alkyleneoxalates); poly(phosphazenes); poly(urethanes); silicones; poly(esters);poly(olefins); copolymers of poly(isobutylene); copolymers ofethylene-alphaolefin; vinyl halide polymers and copolymers such aspoly(vinyl chloride); poly(vinyl ethers) such as poly(vinyl methylether); poly(vinylidene halides) such as, for example, poly(vinylidenechloride); poly(acrylonitrile); poly(vinyl ketones); poly(vinylaromatics) such as poly(styrene); poly(vinyl esters) such as poly(vinylacetate); copolymers of vinyl monomers and olefins such aspoly(ethylene-co-vinyl alcohol) (EVAL), copolymers ofacrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinylacetate; poly(amides) such as Nylon 66 and poly(caprolactam); alkydresins; poly(carbonates); poly(oxymethylenes); poly(imides); poly(esteramides); poly(ethers) including poly(alkylene glycols) such as, forexample, poly(ethylene glycol) and poly(propylene glycol); epoxy resins;polyurethanes; rayon; rayon-triacetate; biomolecules such as, forexample, fibrin, fibrinogen, starch, poly(amino acids); peptides,proteins, gelatin, chondroitin sulfate, dermatan sulfate (a copolymer ofD-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine),collagen, hyaluronic acid, and glycosaminoglycans; other polysaccharidessuch as, for example, poly(N-acetylglucosamine), chitin, chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethylcellulose; and derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. Insome embodiments, other polymers may be selected such that theyspecifically exclude any one or any combination of these polymers.

In some embodiments, the coatings can comprise one or more biodegradablepolymers. Examples of biodegradable polymers include, but are notlimited to, polymers having repeating units such as, for example, anα-hydroxycarboxylic acid, a cyclic diester of an α-hydroxycarboxylicacid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, anepoxide, a glycol, an anhydride, a lactic acid, a glycolic acid, alactide, a glycolide, an ethylene oxide, an ethylene glycol, orcombinations thereof. In some embodiments, the biodegradable polymersinclude, but are not limited to, polyesters, poly(ester amides); aminoacids; PEG and/or alcohol groups, polycaprolactones, poly(L-lactide),poly(D,L-lactide), poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), polydioxanones, polyorthoesters,polyanhydrides, poly(glycolic acid-co-trimethylene carbonate),polyphosphoesters, polyphosphoester urethanes, poly(amino acids),polycyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate),polycarbonates, polyurethanes, copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, PHA-PEG, and any derivatives,analogs, homologues, salts, copolymers and combinations thereof. In someembodiments, the polymers can include poly(glycerol sebacate);tyrosine-derived polycarbonates containing desaminotyrosyl-tyrosinealkyl esters such as, for example, desaminotyrosyl-tyrosine ethyl ester(poly(DTE carbonate)); and any derivatives, analogs, homologues, salts,copolymers and combinations thereof. In some embodiments, the polymersare selected such that they specifically exclude any one or anycombination of these polymers.

In some embodiments, the polymers can be chemically connected bycovalent bonds. In some embodiments, the polymers can be chemicallyconnected to by non-covalent bonds such as, for example, by ionic bonds,inter-molecular attractions, or a combination thereof. In someembodiments, the polymers can be physically connected. In someembodiments, the polymers can be chemically and physically connected.Examples of ionic bonding can include, but are not limited to, ionicbonding of an anionic site to a cationic site between polymers. In someembodiments, an anionic site can be bound to a quaternary amine.Examples of inter-molecular attractions include, but are not limited to,hydrogen bonding such as, for example, the permanent dipole interactionsbetween hydroxyl, amino, carboxyl, amide, and sulfhydryl groups, andcombinations thereof. Examples of physical connections can include, butare not limited to, interpenetrating networks and chain entanglement.The polymers can also be blended or mixed.

The behavior of the polymer matrix can be changed through selection ofany number of factors that provide the desired drug elution, chemicaland physical characteristics of the coatings taught herein. For example,the terminal end groups can be designed to contribute to imparting suchcharacteristics in the polymers. A more hydrophilic end-group canincrease the rate of ingress of water, for example, and likewiseincrease the rate of hydrolysis of the polymer chains, at least in someembodiments. Likewise, a less hydrophilic group can deter in the ingressof water, and slow the rate of hydrolysis, at least in some embodiments.

It should be appreciated that a polymer can be selected to have acidterminal end-groups, hydroxyl terminal end-groups, alkyl-esterend-groups, or a combination thereof. Moreover, a polymer layer can becreated using sub-layers, where the layer can have a sub-layer havingacid groups, a sub-layer having hydroxyl groups, a sub-layer havingester end-groups, or a combination thereof. In fact, the construction ofthe layers and sub-layers can be designed based on thickness ratios todesign a coating that provides a desired characteristic or set ofcharacteristics including, but not limited to, drug-retention time, adesired rate of hydrolysis, a desired glass transition temperature, adesired drug-elution rate, a desired toughness, a desired elasticity, adesired modulus, or a combination thereof.

Molecular weights can also be selected for the polymer in a particularlayer or set of layers in the coating, as a mixture of molecular weightsin a particular layer or set of layers, or as a set of sub-layers, whereeach layer in the sub-layer can have an independently selected molecularweight, mixture of molecular weights, or a combination thereof, wherethe molecular weight or mixture of molecular weights can be the same ordifferent for each sub-layer. And, in many embodiments, a desiredcharacteristic is that the polymers have a structure that remains atleast substantially undegraded during the initial release of the drug.In some embodiments, for example, the drug-retaining layer can comprisea polymer having ester-terminal groups.

In some embodiments, the drug-retaining layer can comprise apoly(lactic-co-glycolic acid) having ester terminal groups, a monomerratio of lactic acid to glycolic acid ranging from about 85:15 to about50:50, and a molecular weight ranging from about 90 KDaltons to about160 KDaltons.

The molecular weights can be selected and tailored for a particularpolymer selection and for a particular coating layer and purpose. Forexample, the polymer can have a molecular weight ranging from about 50KDaltons to about 190 KDaltons, from about 50 KDaltons to about 190KDaltons, from about 50 KDaltons to about 180 KDaltons, from about 60KDaltons to about 170 KDaltons, from about 70 KDaltons to about 160KDaltons, from about 80 KDaltons to about 150 KDaltons, from about 90KDaltons to about 140 KDaltons, from about 90 KDaltons to about 160KDaltons, from about 100 KDaltons to about 160 KDaltons, or any rangetherein.

Without intending to be bound by any theory or mechanism of action, insome embodiments, the drug-reservoir layer is initially implanted in a“drug-absorbing” state and is later transformed into a “drug-release”state over time due to changes in the physical and chemical structureacross the coating in vivo. In the drug-absorbing state, thedrug-reservoir layer has the highest affinity for the drug. In thedrug-release state the drug-reservoir layer has a substantially loweraffinity for the drug. The drug can have the highest solubility in thedrug-reservoir layer in the drug-absorbing state and in the drug-releasestate, the drug can have a substantially lower solubility in thedrug-reservoir layer. In some embodiments, the drug-absorbing state canreflect the state in which the glass transition temperature (Tg) of thedrug-reservoir layer is higher than the temperature of the surroundingtissue/fluid, and the drug-release state can reflect the state at whichthe Tg of drug-reservoir layer is equal to or less than that ofsurrounding tissue/fluid. In some embodiments, coating has a Tg abovethe surrounding tissue temperature of 37 degrees C.

The polymer end-groups can have any structure known to one of skill thatwill provide the desired polymer characteristics for a particularcoating layer or set of layers. In some embodiments, the end-group canbe an ester-terminal group. For example, the polymer structure cancomprise P—CO2R, where P is the polymer backbone and R can be an alkylgroup having from 1 to 4 carbons, from 1 to 20 carbons, from 2 to 12carbons, from 1 to 10, from 2 to 8, from 1 to 6 carbons, from 1 to 5carbons, or any range therein. In some embodiments, R can be anyend-group known to one of skill, with the limitation that R cannotaffect usefulness of the polymer, for example, the ability of thepolymer to be applied as a coating on a desired medical device. In someembodiments, R can be saturated, unsaturated, aromatic, aliphatic, orany combination thereof.

In some embodiments, an R group can be a H; an aliphatic hydrocarbongroup such as, for example, an alkyl, alkenyl, or alkynyl group; anaromatic group such as, for example, an aryl, aralkyl, aralkenyl, ofaralkynyl group; various other groups as defined herein, or acombination thereof.

In some embodiments, the aliphatic radicals have from about 1 to about50 carbon atoms, from about 2 to about 40 carbon atoms, from about 3 toabout 30 carbon atoms, from about 4 to about 20 carbon atoms, from about5 to about 15 carbon atoms, from about 6 to about 10 carbon atoms, andany range therein. In some embodiments, the aromatic radicals have fromabout 4 to about 200 carbon atoms, from about 6 to about 150 carbonatoms, from about 12 to about 120 carbon atoms, from about 18 to about90 carbon atoms, from about 24 to about 60 carbon atoms, and any rangetherein.

The term “alkyl” refers to a straight-chained or branched hydrocarbonchain. Examples of alkyl groups include lower alkyl groups such as, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,t-butyl or iso-hexyl; upper alkyl groups such as for example, n-heptyl,n-octyl, isooctyl, nonyl, decyl, and the like; lower alkylene such as,for example, ethylene, propylene, propylyne, butylenes, butadiene,pentene, n-hexene and iso-hexene; and upper alkylene such as, forexample, n-heptene, n-octene, iso-octene, nonene, decene, and the like.Persons of ordinary skill in the art are familiar with numerousstraight-chained and branched alkyl groups, which are within the scopeof the present invention. In addition, such alkyl groups may alsocontain various substituents in which one or more hydrogen atoms isreplaced by a functional group, or the alkyl groups can contain anin-chain functional group. The phrase “straight-chained or branched”includes any substituted or unsubstituted acyclic carbon-containingcompounds including, but not limited to, alkanes, alkenes and alkynes.

The term “alkenyl” refers to a straight-chained or branched hydrocarbonchain including at least one alkene functionality. The term “alkynyl”refers to a straight-chained or branched carbon-containing chainincluding at least one alkyne functionality. The term “aryl” refers to acarbon-containing ring bearing a system of conjugated double bonds oftencomprising at least six π (pi) electrons. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, anysyl, toluoyl,xylenyl, and the like. The term “aralkyl” refers to an alkyl groupsubstituted with at least one aryl group. The term “aralkenyl” refers toan alkenyl group substituted with at least one aryl group.

A radical is “straight-chained” when it has less than 0.1 mole percentof side chains having 1 or more carbon atoms. In some embodiments, aradical is straight-chained if it has less than 0.01 mole percent ofsuch side chains. In some embodiments, a radical is straight-chained ifit has less than 0.001 mole percent of such side chains. A radical is“branched” when it has more than 0.1 mole percent of side chains having1 or more carbon atoms. In some embodiments, a radical is branched whenit has more than 0.01 mole percent of such side chains. In someembodiments, a radical is branched when it has more than 0.001 molepercent of such side chains.

The terms “radical,” “group,” “functional group,” and “substituent” canbe used interchangeably in some contexts and can be used together tofurther describe a chemical structure. For example, the term “functionalgroup” can refer to a chemical “group” or “radical,” which is a chemicalstructure variable that can be in-chain, pendant and/or terminal to thechemical structure. A functional group may be substituted. Examples ofsubstituents in substituted radicals include, but are not limited to,hydroxyls, alkyls, carboxyls, esters, aminos, amidos, iminos andcombinations thereof. Such a functional group can also, for example,contain a heteroatom. Examples of heteroatoms of the hetero-radicalsinclude, but are not limited to, sulfur, phosphorous, oxygen, nitrogenand combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, alcohols,ethers, phenols, and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetonides, alcohols, alkoxides,bisphenols, carbinols, cresols, diols, enols, enolates, epoxides,ethers, glycols, hydroperoxides, peroxides, phenols, phenolates,phenoxides, pinacols, trioxides, and ynols.

In some embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, aldehydes,ketones, quinones and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetals, acyloins, aldehydes, carbonylcompounds, diosphenols, dypnones, hemiacetals, hemiketals, ketals,ketenes, keto compounds, ketones, quinhydrones, quinomethanes, quinines,and combinations thereof.

In some embodiments, the functional groups can be oxygen-containinggroups including, but not limited to, carboxylic acids, oxoacids,sulfonic acids, acid anhydrides, acid thioanhydrides, acyl groups, acylhalides, acylals, anhydrides, carboxylic acids, cyclic acid anhydrides,cyclic anhydrides, esters, fulgides, lactides, lactols, lactones,macrolides, naphthenic acids, ortho acids, ortho esters, oxo carboxylicacids, peroxy acids, and combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing one nitrogen such as,for example, aldimines, aldoximes, alkoxyamines, amic acids, amides,amines, amine oxides, amine ylides, carbamates, hemiaminals,carbonitriles, carboxamides, isocyanides, cyanates, isocyanates,diisocyanates, cyanides, cyanohydrins, diacylamines, enamines,fulminates, hemiaminals, hydroxamic acids, hydroximic acids,hydroxylamines, imides, imidic acids, imidines, imines, oximes,isoureas, ketenimines, ketimines, ketoximes, lactams, lactims, nitriles,nitro, nitroso, nitrosolic acids, oxime O-ethers, quaternary ammoniumcompounds, quinone imines, quinonoximes, azomethines, ureides,urethanes, and combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing two or more nitrogenssuch as, for example, aldazines, amide hydrazones, amide oximes,amidines, amidrazones, aminals, amine imides, amine imines, isodiazenes,azans, azides, azo imides, azines, azo compounds, azomethine imides,azoxy compounds, carbodiimides, carboxamidines, diamidides, diazocompounds, diazoamino compounds, diazoates, diazooxides, formamidinedisulfides, formazans, hydrazides, hydrazide hydrazones, hydrazideimides, hydrazidines, hydrazines, hydrazo compounds, hydrazones,ketazines, nitramines, nitrile imines, nitrimines, nitrolic acids,nitrosamides, nitrosamines, nitrosimines, ortho amides, semicarbazones,semioxamazones, triazanes, triazenes, and combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, sulfur-containing groups such as sulfones, sulfides,sulfinamides, sulfilimines, sulfimides, sulfinamides, sulfinamidines,sulfines, sulfinic acids, sulfinic anhydrides, sulfinylamines,sulfonamides, sulfones, sulfonediimines, sulfonic acids, sulfonicanhydrides, sulfoxides, sulfoximides, sulphur diimides, thio,thioacetals, thioaldehydes, thioanhydrides, thiocarboxylic acids,thiocyanates, thioether, thiohemiacetals, thioketones, thiol, thiolates,xanthic acids, and combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, silyl groups, halogens, selenoethers, trifluoromethyls,thio-derivatives of urethanes where at least one oxygen atom is replacedby a sulfur atom, phosphoryls, phosphonates, phosphinates, andcombinations thereof. In some embodiments, the functional groups arecapable of free-radical polymerization and can include, but are notlimited to, ethylenically unsaturated groups such as, for example,allyl, vinyl, acryloyl and methacrylol, and maleate and maleimido; andcombinations thereof. In some embodiments, the functional groups includehalides. In some embodiments, the functional group may include lightscattering groups, magnetic groups, nanogold, other proteins, a solidmatrix, radiolabels, carbohydrates, and combinations thereof.

The coating may at least substantially promote development of thefunctional endothelium as the source of the thrombomodulin when comparedto a control development of such endothelium formation observedfollowing CBD or TCHation of a metal or polymer drug-eluting medicaldevice. In some embodiments, the medical device comprises an CBD or TCH.

One of skill will appreciate that a functional endothelium exists, or ispromoted, for example, where the amount of thrombomodulin in thefunctional endothelium is in a quantity sufficient to show a statisticaldifference in an amount of thrombus formation when compared to a controldevelopment of such an endothelium, or lack thereof, observed followingCBD or TCHation of a control metal or polymer drug-eluting device. Insome embodiments, the functional endothelium has been promoted where itcan produce an amount of thrombomodulin that is substantially greaterthan an amount of thrombomodulin observed from a control medical device.An amount of thrombomodulin is “substantially greater” when the desiredanti-thrombus effect is statistically improved over that observed from acontrol medical device. In some embodiments, a functional endotheliumexists, or has been promoted, where the desired effects of thrombusinhibition, restenosis inhibition, and/or blood flow improvement fromthe presence of thrombomodulin becomes statistically observable whencompared to a control development of such endothelium formation observedfollowing CBD or TCHation of a metal or polymer drug-eluting medicaldevice that does not delay the onset of drug-elution for at least 5, 10,12, 14, 15, 20, 25, 30, 45, 60, 75, or 90 days, or any range therein.

In addition, the coating may at least substantially inhibit developmentof a hyperproliferative tissue when compared to a control development ofsuch hyperproliferative tissue observed following CBD or TCHation of ametal or polymer medical device that does not elute a drug. One of skillwill appreciate, for example, that hyperproliferative tissue growthincludes a growth of tissue beyond what is normal and healthy. It cancause adverse effects on the function or physiology of the subject.

The inhibition of the development of a hyperproliferative tissue canoccur, or be promoted, when the amount of such tissue is in a quantitysufficient to show a statistical difference in an amount of tissueformation when compared to a control development of such an tissue, orlack thereof, observed following CBD or TCHation of a control metal orpolymer medical device that does not elute a drug. In some embodiments,the amount of hyperproliferative tissue produced from the control deviceis substantially greater than an amount of tissue observed from amedical device having a coating taught herein. An amount of tissue canbe considered “substantially greater” when the measured amount isstatistically greater. In some embodiments, restenosis is inhibited byat least 5, 10, 12, 14, 15, 20, 25, 30, 45, 60, 75, 90, 95, 99, 100percent, or any amount therein, when compared to a control developmentof such restenosis formation observed following CBD or TCHation of ametal or polymer medical device that does not elute a drug.

The coatings can be designed for a predetermined delay time and releaserate of the drug. As described above, layers and sub-layers of coatingscan be designed to have a different composition to impart more controlover drug elution, coating hydrolysis, coating strength and integrity,other physical traits, and other such coating characteristics known toone of skill. In some embodiments, for example, the drug-reservoir layercan further comprise an accelerant layer to accelerate the time to onsetof drug elution. In fact, in some embodiments, the accelerant layer canhave a poly(lactic-co-glycolic acid) with acid terminal groups, amonomer ratio of lactic acid to glycolic acid that ranges from about85:15 to about 50:50, and a molecular weight that ranges from about 90KDaltons to about 120 KDaltons.

And, as described above, other variables, such as layer or sub-layerthickness, and/or thickness ratios between layers and/or sub-layers, canbe used to obtain a desired delay time for drug release, release rate ofthe drug, fluid uptake in the coating, as well as coating strength,integrity, and the like. In some embodiments, the thickness of thecoating can range from about 2 microns to about 9 microns, from about 1micron to about 40 microns, from about 1 micron to about 30 microns,from about 2 microns to about 38 microns, from about 3 microns to about36 microns, from about 4 microns to about 34 microns, from about 5microns to about 7 microns, from about 4 microns to about 6 microns, orany range therein. In some embodiments, the thickness of the coating isless than 12 microns, less than 11 microns, less than 9 microns, lessthan 8 microns, less than 7 microns, less than 6 microns, less than 5microns, or any range therein, such as, for example, from 7 microns to12 microns, 9 microns to 12 microns, or 7 microns to 9 microns. In someembodiments, each layer or sub-layer can range from about 0.1 micron toabout 10 microns, from about 0.1 micron to about 7 microns, from about0.1 micron to about 5 microns, from about 0.1 micron to 3 microns, fromabout 0.1 micron to about 2 microns, from about 0.1 micron to about 0.9microns, from about 0.1 micron to about 0.8 microns, from about 0.1micron to about 0.7 microns, from about 0.1 micron to about 0.6 microns,from about 0.1 micron to about 0.5 microns, from about 0.1 micron toabout 0.4 microns, from about 0.1 micron to about 0.3 microns, fromabout 0.3 micron to about 0.8 microns, from about 0.2 microns to about 5microns, from about 0.2 microns to about 4 microns, from about 0.3microns to about 3 microns, from about 0.5 microns to about 5 microns,from about 0.6 microns to about 3 microns from about 1 micron to about 3microns, or any range therein.

In some embodiments, for example, the thickness ratio of thedrug-reservoir layer to the drug-containing layer can range from about4:1 to about 10:1, from about 4:1 to about 7:1, from about 2:1 to about12:1, from about 3:1 to about 11:1, from about 5:1 to about 10:1, fromabout 2:1 to about 8:1, from about 4:1 to about 6:1, or any rangetherein. In some embodiments, the ratio can be a mass ratio, where themass of the drug-reservoir layer to the mass of the drug-containinglayer can range from 3:1 to 20:1, from 4:1 to 16:1, from 5:1 to 15:1,from 6:1 to 10:1, or any range therein.

In some embodiments thinner coatings and desired ratios can be achievedusing higher percentages of drug in the drug-containing layer, where insome embodiments, the drug-containing layer is composed of 100, 99, 98,97, 96, 95, 94, 93, 92, 91, 90 percent drug, or any range therein. Thedrug-containing layer can range from about 0.05 to about 5 microns, fromabout 0.03 to about 3 microns, from about 0.1 to about 2 microns, or anyrange therein in thickness, in some embodiments.

The relative hydrophobicity or hydrophilicity can also impart desireddrug retention and elution behavior from the coating. For example, themiscibility of the drug in a coating can be preselected to affect therate of drug migration in the coating, and/or elution from the coating.In some embodiments, the drug can be selected to be miscible in acoating to increase retention time in the coating. Likewise, in someembodiments, the drug can be selected to be less miscible, orimmiscible, in a coating to decrease retention time in the coating.

As such, the teachings are generally directed to a method of inhibitingthe formation of hyperproliferative tissue and promoting the formationof a functional endothelium after CBD or TCHation of a medical device ina subject. The method can comprise applying a therapeutic coating on amedical device and CBD or TCHing the device in the subject. In someembodiments, the coating can comprise a biodegradable drug-containinglayer that (i) is positioned over a surface of a medical device and (ii)serves as a source of a drug that functions as an anti-proliferativeagent in a subject; and, a biodegradable drug-reservoir layer positionedover a surface of the drug-containing layer and comprising adrug-retaining layer, the drug-retaining layer remaining void orsubstantially void of the drug at a time of CBD or TCHation in thesubject and functioning to retain and at least substantially block aninitial release of the drug into the subject for a time sufficient toform a functional endothelium over the surface of the medical device,the functional endothelium providing a source of thrombomodulin to thesubject.

One of skill will appreciate that a coating can be applied using anyone, or any combination, of methods known in the art, where the terms“form” and “apply” can be used interchangeably, in some embodiments. Thecompositions can be in the form of coatings for medical devices such as,for example, a balloon-expandable breast CBD or TCH. There are manycoating configurations possible, and each configuration can include anynumber and combination of layers. In some embodiments, the coatings cancomprise one or a combination of the following four types of layers: (a)an agent layer, which may comprise a polymer and an agent or,alternatively, a polymer free agent; (b) an optional primer layer, whichmay improve adhesion of subsequent layers on the CBD or TCHablesubstrate or on a previously formed layer; (c) an optional topcoatlayer, which may serve as a way of controlling the rate of release of anagent; and (d) an optional biocompatible finishing layer, which mayimprove the biocompatibility of the coating.

In some embodiments, any one or any combination of layers can be used.And, each layer can be applied to an CBD or TCHable substrate, forexample, by any method including, but not limited to, dipping, spraying,pouring, brushing, spin-coating, roller coating, meniscus coating,powder coating, inkjet-type application or a combination thereof. In oneexample, each of the layers can be formed on an CBD or TCH by dissolvingone or more biodegradable polymers, optionally with a non-biodegradablepolymer, in one or more solvents and either (i) spraying the solution onthe CBD or TCH or (ii) dipping the CBD or TCH in the solution. In thisexample, a dry coating of biodegradable polymer may be formed on the CBDor TCH when the solvent evaporates.

The formation of each layer may involve use of a casting solvent. Acasting solvent is a liquid medium within which a polymer can besolubilized to form a solution that may be applied as a coating on asubstrate. The casting solvent must be selected to avoid adverselyaffecting an underlying material such as, for example, an underlyingprimer layer or a bare CBD or TCH structure. In one example, a materialused to form the primer layer is soluble in a highly polar castingsolvent but is reasonably insoluble in a low polarity casting solvent. Amaterial is “reasonably insoluble” in a solvent when the material doesnot solubilize to an extent great enough to significantly affect theperformance of the resulting product, meaning that the product can stillbe used for its intended purpose. In this example, an overlying agentlayer that is soluble in a low polarity casting solvent can be appliedto the underlying primer layer without disrupting the structure ofprimer layer.

The casting solvent may be chosen based on several criteria including,for example, its polarity, ability to hydrogen bond, molecular size,volatility, biocompatibility, reactivity and purity. Other physicalcharacteristics of the casting solvent may also be taken into accountincluding the solubility limit of the polymer in the casting solvent,the presence of oxygen and other gases in the casting solvent, theviscosity and vapor pressure of the combined casting solvent andpolymer, the ability of the casting solvent to diffuse through anunderlying material, and the thermal stability of the casting solvent.

One of skill in the art has access to scientific literature and dataregarding the solubility of a wide variety of polymers. Furthermore, oneof skill in the art will appreciate that the choice of casting solventmay begin empirically by calculating the Gibb's free energy ofdissolution using available thermodynamic data. Such calculations allowfor a preliminary selection of potential solvents to test in alaboratory. It is recognized that process conditions can affect thechemical structure of the underlying materials and, thus, affect theirsolubility in a casting solvent. It is also recognized that the kineticsof dissolution are a factor to consider when selecting a castingsolvent, because a slow dissolution of an underlying material, forexample, may not affect the performance characteristics of a productwhere the product is produced relatively quickly.

Casting solvents for use in the present invention include, but are notlimited to, DMAC, DMF, THF, cyclohexanone, xylene, toluene, acetone,i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether,methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane.Solvent mixtures can be used as well. Examples of the mixtures include,but are not limited to, DMAC and methanol (50:50 w/w); water,i-propanol, and DMAC (10:3:87 w/w); i-propanol and DMAC (80:20, 50:50,or 20:80 w/w); acetone and cyclohexanone (80:20, 50:50, or 20:80 w/w);acetone and xylene (50:50 w/w); acetone, xylene and FLUX REMOVER AMS(93.7% 3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance is methanolwith trace amounts of nitromethane; Tech Spray, InC) (10:40:50 w/w); and1,1,2-trichloroethane and chloroform (80:20 w/w).

It should be appreciated that a process of forming a medical article orcoating can include additional process steps such as, for example, theuse of energy such as heat, electromagnetic radiation, electron beam,ion or charged particle beam, neutral-atom beam, and chemical energy.The process of drying can be accelerated by using higher temperatures.

A medical article or coating can also be annealed to enhance themechanical properties of the composition. Annealing can be used to helpreduce part stress and can provide an extra measure of safety inapplications such as complex medical devices, where stress-crackingfailures can be critical. The annealing can occur at a temperature thatranges from about 30 degrees C. to about 200 degrees C., from about 35degrees C. to about 190 degrees C., from about 40 degrees C. to about180 degrees C., from about 45 degrees C. to about 175 degrees C., or anyrange therein. The annealing time can range from about 1 second to about60 seconds, from about 1 minute to about 60 minutes, from about 2 minuteto about 45 minutes, from about 3 minute to about 30 minutes, from about5 minute to about 20 minutes, or any range therein. The annealing canalso occur by cycling heating with cooling, wherein the total time takenfor heating and cooling is the annealing cycle time.

In some embodiments, the drug-containing layer can be applied as asolvent mixture and the solvent can be dried after application using asubstantially non-reactive heated gas. The drying can serve to at leastsubstantially inhibit mobilization of the drug from the drug-containinglayer during application of additional layers in the formation of thecoating. The amount of mobilization of the drug can be considered“substantially inhibited” when the measured amount of mobilization ofthe drug from the drug-containing layer is statistically less than ifthe drying procedure was not used as taught herein.

The application of the sub-layers can be used to at least substantiallypromote a retention of the drug in the drug-containing layer duringformation of the coating when compared to such a coating without theapplication of the sub-layers. The amount of retention of the drug canbe considered “substantially promoted” when the measured amount ofretention of the drug from the drug-containing layer is statisticallygreater than if the sub-layer application as taught herein was not used.

In some embodiments, the drug-retaining layer can comprise at least onesub-layer having a thickness of less than or equal to 3 microns, where arepeated application of the sub-layer can be used to form thicknesses ofgreater than 3 microns. In some embodiments, the accelerant layer can bepositioned between the drug-containing layer and the remainder of thedrug-retaining layer, is more hydrophilic than the remainder of thedrug-retaining layer, and comprises at least one sub-layer having athickness of less than or equal to 3 microns, where a repeatedapplication the sub-layer is used to form thicknesses of greater than 3microns. The accelerant layer can contain some of the drug. In someembodiments, the drug composes less than 30, 25, 20, 15, 10, 7, 5, 4, 3,2, 1 percent, or any amount therein, of the accelerant layer. And, insome embodiments the drug composes less than 10 percent of theaccelerant layer.

The coatings can be heterogeneous in morphology. For example, ahydrophobic layer can contain hydrophilic regions. Likewise, a morehydrophilic coating can have hydrophobic regions. The hydrophilicregions can be in the form of isolated packages of material, or“islands” in some embodiments, where the isolated hydrophilic packagecan add to the water absorption rate, and thus hydrolysis rate, of thecoating. The isolated packages may be added during the coating processas droplets, in some embodiments. The coatings taught herein can, insome embodiments, further comprise pockets of hydrophilic material inthe drug-retaining layer, wherein the hydrophilic material can comprisea second drug. There can be one or more such pockets, and the pocketscan be positioned anywhere throughout the coating. In some embodiments,one or more hydrophilic pockets are positioned in the drug reservoirlayer and, in some embodiments, one or more hydrophilic pockets arepositioned in the drug-retaining layer. In some embodiments, thehydrophilic pockets comprise a drug selected from the group consistingof dextran, heparin, ticlopidine, chlopidogrel, enoxaparin, dalteparin,hirudin, bivalirudin, argatroban, and danparoid.

The coating can be applied to a surface of a medical device using, forexample, wet chemistry and acetone as a solvent with techniques known toone of skill. At least one drug and polymer is dissolved into thevolatile solvent to form a drug solution, and the drug can be ananti-proliferative, such as rapamycin. The volatile solvent can beacetone, dichloromethane, or a mixture of the two solvents.

In one example, about 1-2 micron of a drug-containing layer can becovered with a 1-3 micron accelerant layer made of acid terminated 75/25monomer ratio PLGA having a molecular weight of 90-120 KDalton, and theaccelerant layer can be covered with about 6-12 microns of esterterminated 75/25 monomer ratio PLGA having a molecular weight of 100-160KDalton. This unique and novel combination of compositions in differentlayers, as well as the relative thicknesses and positioning of thelayers, can provide a coating having a desired delay in the onset ofdrug elution. The elution, in fact, can be delayed for a designed,prolonged period of time, at which time the drug release is fast enoughto have a therapeutic effect. The coating is robust, maintainingfunctional integrity through stresses and strains of assembly anddeployment. And, the coating can maintain a low enough profile of theCBD or TCH for ease of delivery and introducing less foreign materialinto the body.

The following is an example of a process that can be used to createcomposite elution layers, a process comprising multiple sub-layerapplications, such as those described herein. The drug is added to thesolvent for wet chemistry application, and the drug-containing layer maybe applied to the surface of the device. The drug-containing layer canbe 120 nanometers and 6 microns, 200 nanometers and 3 microns, 0.7-1.1microns, or any range therein, thick in some embodiments. Thedrug-containing layer is then dried with convection of a non-reactivegas, such as nitrogen, at a temperature elevated above room temperature.

The accelerant layer polymer is mixed with a solvent for wet chemistryapplication, and the accelerant layer is created by layering multiplesub-layers of the same material. Each sub-layer is coated onto previouslayer and dried with convection of gas as described in above using adrying time of about 1-2 hours before coating the next sub-layer/layer.The accelerant layer can be about 1-2 microns thick and composed of50:50 PLGA with acid terminal end-groups. In some embodiments, theaccelerant layer can be about 3-5 microns thick and composed of 2-3sub-layers of 75:25 PLGA with acid terminal end-groups. And, in someembodiments, the accelerant layer can be between about 120 nanometersand 6 microns, 400 nanometers and 4 microns, 500 nanometers and 5microns, or any range therein. Moreover, the concentration of the drugin the accelerant layer can be less than 50% of the drug-containinglayer before CBD or TCHation in some embodiments.

The drug-retaining layer can then be prepared and coated onto theaccelerant layer and dried. The drug-retaining layer is applied bylayering multiple sub-layers of the same material. Each sub-layer iscoated onto previous layer and dried using convection of gas asdescribed above with drying times of about 1-2 hours before coating thenext sub-layer/layer. The drug-retaining layer can be about 3-5 timesthe thickness of the accelerant layer, in some embodiments, if theaccelerant layer is composed of 50:50 PLGA having an ester terminalend-group in some embodiments. In some embodiments, the thickness of thedrug-retaining layer can be about 0.2-2 times that of the accelerantlayer, if the accelerant layer is composed of 75:25 PLGA having an esterterminal end-group. The entire assembly may then be packaged andsterilized for deployment.

One of skill will appreciate that any non-reactive or substantiallynon-reactive gas can be used including, but not limited to, nitrogen,carbon dioxide, or a noble gas. The heated gas's temperature can be, forexample, between about 70 degrees F. and the drug's melting point. Insome embodiments, the gas's temperature can be between about 70 degreesF. and 240 degrees F., from 140-190 degrees F., or any range therein.The specified drying time can be, for example, between about 0 minutesand 3 hours, 10-30 minutes, 30 minutes and 1 hour, 15 minutes and 2hours, or any range therein. The gas surface flow rate can be betweenabout 40 and 500 inches per second, 50 and 400 inches per second, 100and 500 inches per second, or any range therein. In some embodiments,the gas surface flow rate is 90-150 inches/sec

It should be appreciated that, in some embodiments, the term “agent” or“drug” can be used interchangeably. An “agent” or “drug” can be amoiety, for example, that may be bioactive, biobeneficial, diagnostic,plasticizing, or have a combination of these characteristics. A “moiety”can be a functional group composed of at least 1 atom, a bonded residuein a macromolecule, an individual unit in a copolymer or an entirepolymeric block. It is to be appreciated that any medical articles thatcan be improved through the teachings described herein are within thescope the invention.

A “bioactive agent” is a moiety that can be combined with a polymer andprovides a therapeutic effect, a prophylactic effect, both a therapeuticand a prophylactic effect, or other biologically active effect within asubject. Moreover, the bioactive agents of the present invention mayremain linked to a portion of the polymer or be released from thepolymer. A “biobeneficial agent” is an agent that can be combined with apolymer and provide a biological benefit within a subject withoutnecessarily being released from the polymer.

In one example, a biological benefit may be that the polymer or coatingbecomes non-thrombogenic, such that protein absorption is inhibited orprevented to avoid formation of a thromboembolism; promotes healing,such that endothelialization within a blood vessel is not exuberant butrather forms a healthy and functional endothelial layer; or isnon-inflammatory, such that the biobeneficial agent acts as a biomimicto passively avoid attracting monocytes and neutrophils, which couldlead to an event or cascade of events that create inflammation.

A “diagnostic agent” is a type of bioactive agent that can be used, forexample, in diagnosing the presence, nature, or extent of a disease ormedical condition in a subject. In one embodiment, a diagnostic agentcan be any agent that may be used in connection with methods for imagingan internal region of a patient and/or diagnosing the presence orabsence of a disease in a patient. Diagnostic agents include, forexample, contrast agents for use in connection with ultrasound imaging,magnetic resonance imaging (MRI), nuclear magnetic resonance (NMR),computed tomography (CT), electron spin resonance (ESR), nuclear medicalimaging, optical imaging, elastography, and radiofrequency (RF) andmicrowave lasers. Diagnostic agents may also include any other agentsuseful in facilitating diagnosis of a disease or other condition in apatient, whether or not imaging methodology is employed.

Examples of biobeneficial agents include, but are not limited to, manyof the polymers listed above such as, for example,carboxymethylcellulose; poly(alkylene glycols) such as, for example,PEG; poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane sulfonicacid); poly(styrene sulfonate); sulfonated polysaccharides such as, forexample, sulfonated dextran; sulfated polysaccharides such as, forexample, sulfated dextran and dermatan sulfate; and glycosaminoglycanssuch as, for example, hyaluronic acid and heparin; and any derivatives,analogs, homologues, congeners, salts, copolymers and combinationsthereof. In some embodiments, the biobeneficial agents can be prohealingsuch as, for example, poly(ester amides), elastin, silk-elastin,collagen, atrial natriuretic peptide (ANP); and peptide sequences suchas, for example, those comprising Arg-Gly-Asp (RGD). In otherembodiments, the biobeneficial agents can be non-thrombotics such as,for example, thrombomodulin; and antimicrobials such as, for example,the organosilanes. It is to be appreciated that one skilled in the artshould recognize that some of the groups, subgroups, and individualbiobeneficial agents may not be used in some embodiments of the presentinvention.

Examples of heparin derivatives include, but are not limited to, earthmetal salts of heparin such as, for example, sodium heparin, potassiumheparin, lithium heparin, calcium heparin, magnesium heparin, and lowmolecular weight heparin. Other examples of heparin derivatives include,but are not limited to, heparin sulfate, heparinoids, heparin-basedcompounds and heparin derivatized with hydrophobic materials.

Examples of hyaluronic acid derivates include, but are not limited to,sulfated hyaluronic acid such as, for example, O-sulphated orN-sulphated derivatives; esters of hyaluronic acid wherein the esterscan be aliphatic, aromatic, arylaliphatic, cycloaliphatic, heterocyclicor a combination thereof; crosslinked esters of hyaluronic acid whereinthe crosslinks can be formed with hydroxyl groups of a polysaccharidechain; crosslinked esters of hyaluronic acid wherein the crosslinks canbe formed with polyalcohols that are aliphatic, aromatic, arylaliphatic,cycloaliphatic, heterocyclic, or a combination thereof; hemiesters ofsuccinic acid or heavy metal salts thereof; quaternary ammonium salts ofhyaluronic acid or derivatives such as, for example, the O-sulphated orN-sulphated derivatives.

Examples of poly(alkylene glycols) include, but are not limited to, PEG,mPEG, poly(ethylene oxide), poly(propylene glycol)(PPG),poly(tetramethylene glycol), and any derivatives, analogs, homologues,congeners, salts, copolymers and combinations thereof. In someembodiments, the poly(alkylene glycol) is PEG. In other embodiments, thepoly(alkylene glycol) is mPEG. In other embodiments, the poly(alkyleneglycol) is poly(ethylene glycol-co-hydroxybutyrate).

The copolymers that may be used as biobeneficial agents include, but arenot limited to, any derivatives, analogs, homologues, congeners, salts,copolymers and combinations of the foregoing examples of agents.Examples of copolymers that may be used as biobeneficial agents in theteachings herein include, but are not limited to, dermatan sulfate,which is a copolymer of D-glucuronic acid or L-iduronic acid andN-acetyl-D-galactosamine; poly(ethylene oxide-co-propylene oxide);copolymers of PEG and hyaluronic acid; copolymers of PEG and heparin;copolymers of PEG and hirudin; graft copolymers of poly(L-lysine) andPEG; copolymers of PEG and a poly(hydroxyalkanoate) such as, forexample, poly(ethylene glycol-co-hydroxybutyrate); and any derivatives,analogs, congeners, salts, or combinations thereof. In some embodiments,the copolymer that may be used as a biobeneficial agent can be acopolymer of PEG and hyaluronic acid, a copolymer of PEG and hirudin,and any derivative, analog, congener, salt, copolymer or combinationthereof. In other embodiments, the copolymer that may be used as abiobeneficial agent is a copolymer of PEG and a poly(hydroxyalkanoate)such as, for example, poly(hydroxybutyrate); and any derivative, analog,congener, salt, copolymer or combination thereof.

The bioactive agents can be any moiety capable of contributing to atherapeutic effect, a prophylactic effect, both a therapeutic andprophylactic effect, or other biologically active effect in a mammal.The agent can also have diagnostic properties. The bioactive agentsinclude, but are not limited to, small molecules, nucleotides,oligonucleotides, polynucleotides, amino acids, oligopeptides,polypeptides, and proteins. In one example, the bioactive agent inhibitsthe activity of vascular smooth muscle cells. In another example, thebioactive agent controls migration or proliferation of smooth musclecells to inhibit restenosis.

Bioactive agents include, but are not limited to, antiproliferatives,antineoplastics, antimitotics, anti-inflammatories, antiplatelets,anticoagulants, antifibrins, antithrombins, antibiotics, antiallergics,antioxidants, and any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof. It is to beappreciated that one skilled in the art should recognize that some ofthe groups, subgroups, and individual bioactive agents may not be usedin some embodiments of the present invention.

Antiproliferatives include, for example, actinomycin D, actinomycin IV,actinomycin IL actinomycin X1, actinomycin C1, and dactinomycin(COSMEGEN, Merck & Co., InC). Antineoplastics or antimitotics include,for example, paclitaxel (TAXOL, Bristol-Myers Squibb Co.), docetaxel(TAXOTERE, Aventis S.A.), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (ADRIAMYCIN,Pfizer, InC) and mitomycin (MUTAMYCIN, Bristol-Myers Squibb Co.), andany prodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Antiplatelets, anticoagulants, antifibrin, and antithrombins include,for example, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethyl ketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors (ANGIOMAX, Biogen, InC), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof.

Cytostatic or antiproliferative agents include, for example,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN and CAPOZIDE, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL and PRINZIDE, Merck & Co., InC); calcium channelblockers such as nifedipine; colchicines; fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid); histamine antagonists;lovastatin (MEVACOR, Merck & Co., InC); monoclonal antibodies including,but not limited to, antibodies specific for Platelet-Derived GrowthFactor (PDGF) receptors; nitroprusside; phosphodiesterase inhibitors;prostaglandin inhibitors; suramin; serotonin blockers; steroids;thioprotease inhibitors; PDGF antagonists including, but not limited to,triazolopyrimidine; and nitric oxide, and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof. Antiallergic agents include, but are not limited to, pemirolastpotassium (ALAMAST, Santen, InC), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof.

Other bioactive agents useful in the teachings herein include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; 42-Epi-(tetrazoylyl) rapamycin (ABT-578); everolimus;tacrolimus; 40-O-(2-hydroxy)ethyl-rapamycin;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs; estradiol; clobetasol; idoxifen; tazarotene;alpha-interferon; host cells such as epithelial cells; geneticallyengineered epithelial cells; dexamethasone; and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, freeradical (4-hydroxy-TEMPO),2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, freeradical; 4-carboxy-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-carboxy-TEMPO); 16-doxyl-stearic acid, free radical; superoxidedismutase mimic (SODm) and any analogs, homologues, congeners,derivatives, salts and combinations thereof. Nitric oxide donorsinclude, but are not limited to, S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazeniumdiolates such as spermine diazenium diolate and any analogs, homologues,congeners, derivatives, salts and combinations thereof. The drugs elutedfrom the coatings taught herein can function as an anti-proliferative orimmunosuppressant. In some embodiments, the drug can be rapamycin or aderivative of rapamycin. And, in some embodiments, the drug can beselected from the group consisting of fluoroquinolone, paclitaxel,rapamycin, sirolimus, everolimus, biolimus, zotarolimus, tacrolimus,fibroblast growth factor (bFGF), rapamycin analogs, antisensedexamethasone, angiopeptin, BATIMISTAT, tranilast, transilast,halofuginon, acetylsalicylic acid, hirudin, steroids, ibuprofen,antimicrobials, antibiotics, actinomycin D, tissue plasma activators,and estradiol. One of skill will appreciate that agents that affectvascular smooth muscle cell (VSMC) proliferation or migration can alsobe used in some embodiments, including, but not limited to transcriptionfactor E2F1.

The agents of the present invention can be used alone or in combinationwith other agents to obtain other desired functions of the polymericcompositions. The amounts of the agents that compose the polymericcompositions vary according to a variety of factors including, but notlimited to, the biological activity of the agent; the age, body weight,response, or the past medical history of the subject; the type ofatherosclerotic disease; the presence of systemic diseases such as, forexample, diabetes; the pharmacokinetic and pharmacodynamic effects ofthe agents or combination of agents; and the design of the compositionsfor sustained release of the agents. Factors such as these are routinelyconsidered by one of skill in the art when administering an agent to asubject in a desired amount to obtain a desired effect. In someembodiments, the desired amount is termed an “effective amount,” wherethe amount administered elicits a desired response. In some embodiments,the effective amount can be a “therapeutically effective amount”,administered in an amount that prevents, inhibits, or ameliorates thesymptoms of a disease.

It is to be appreciated that the design of a composition for drugrelease can be dependent on a variety of factors such as, for example,the therapeutic, prophylactic, ameliorative or diagnostic needs of apatient or condition. In some embodiments, the agent can comprise anantiproliferative and should have a sustained release ranging from about1 week to about 10 weeks, from about 2 weeks to about 8 weeks, fromabout 3 weeks to about 7 weeks, from about 4 weeks to about 6 weeks, andany range therein. In some embodiments, the agent can comprise ananti-inflammatory and should have a sustained release ranging from about6 hours to about 3 weeks, from about 12 hours to about 2 weeks, fromabout 18 hours to about 10 days, from about 1 day to about 7 days, fromabout 2 days to about 6 days, or any range therein. In general, thesustained release should range from about 4 hours to about 12 weeks;alternatively, from about 6 hours to about 10 weeks; or from about 1 dayto about 8 weeks.

Effective amounts, for example, may be extrapolated from in vitro oranimal model systems. In some embodiments, the agent or combination ofagents have a concentration that ranges from about 0.001% to about 75%;from about 0.01% to about 70%; from about 0.1% to about 60%; from about0.25% to about 60%; from about 0.5% to about 50%; from about 0.75% toabout 40%; from about 1.0% to about 30%; from about 2% to about 20%; andany range therein, where the percentage is based on the total weight ofthe polymer and agent or combination of agents.

The medical devices discussed herein can be any devices known to one ofskill to benefit from the teachings provided. A medical device, forexample, can be comprised of a metal or an alloy, including, but notlimited to, ELASTINITE, NITINOL, stainless steel, tantalum,tantalum-based alloys, nickel-titanium alloy, platinum, platinum-basedalloys such as, for example, platinum-iridium alloys, iridium, gold,magnesium, titanium, titanium-based alloys, zirconium-based alloys,alloys comprising cobalt and chromium (ELGILOY, Elgiloy SpecialtyMetals, InC; MP35N and MP20N, SPS Technologies) or combinations thereof.The tradenames “MP35N” and “MP20N” describe alloys of cobalt, nickel,chromium and molybdenum. The MP3SN consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. The MP20N consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Medical devices withstructural components that, are comprised of bioabsorbable polymers orbiostable polymers are also included within the scope of the presentinvention.

The terms “plasticizer” and “plasticizing agent” can be usedinterchangeably in the teachings herein, and refer to any agent,including any agent described above, where the agent can be added to apolymeric composition to modify the mechanical properties of thecomposition or a product formed from the composition. Plasticizers canbe added, for example, to reduce crystallinity, lower theglass-transition temperature (Tg), or reduce the intermolecular forcesbetween polymers, with design goals that may include, but are notlimited to, enhancing mobility between polymer chains in thecomposition. The mechanical properties that are modified include, butare not limited to, Young's modulus, impact resistance (toughness),tensile strength, and tear strength. Impact resistance, or “toughness,”is a measure of energy absorbed during fracture of a polymer sample ofstandard dimensions and geometry when subjected to very rapid impactloading. Toughness can be measured using Charpy and Izod impact tests toassess the brittleness of a material.

A plasticizer can be monomeric, polymeric, co-polymeric, or acombination thereof, and can be combined with a polymeric composition inthe same manner as described above for the biobeneficial and bioactiveagents. Plasticization and solubility are analogous in the sense thatselecting a plasticizer involves considerations similar to selecting asolvent such as, for example, polarity. Furthermore, plasticization canalso be provided through covalent bonding by changing the molecularstructure of the polymer through copolymerization.

Examples of plasticizing agents include, but are not limited to, lowmolecular weight polymers such as single-block polymers, multi-blockpolymers, and copolymers; oligomers such as ethyl-terminated oligomersof lactic acid; small organic molecules; hydrogen bond forming organiccompounds with and without hydroxyl groups; polyols such as lowmolecular weight polyols having aliphatic hydroxyls; alkanols such asbutanols, pentanols and hexanols; sugar alcohols and anhydrides of sugaralcohols; polyethers such as poly(alkylene glycols); esters such ascitrates, phthalates, sebacates and adipates; polyesters; aliphaticacids; proteins such as animal proteins and vegetable proteins; oilssuch as, for example, the vegetable oils and animal oils; silicones;acetylated monoglycerides; amides; acetamides; sulfoxides; sulfones;pyrrolidones; oxa acids; diglycolic acids; and any analogs, derivatives,copolymers and combinations thereof.

In some embodiments, the plasticizers include, but are not limited toother polyols such as, for example, caprolactone diol, caprolactonetriol, sorbitol, erythritol, glucidol, mannitol, sorbitol, sucrose, andtrimethylol propane. In other embodiments, the plasticizers include, butare not limited to, glycols such as, for example, ethylene glycol,diethylene glycol, triethylene glycol, tetraethylene glycol, propyleneglycol, butylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, pentamethylene glycol, hexamethylene glycol;glycol-ethers such as, for example, monopropylene glycol monoisopropylether, propylene glycol monoethyl ether, ethylene glycol monoethylether, and diethylene glycol monoethyl ether; and any analogs,derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers include, but are not limited toesters such as glycol esters such as, for example, diethylene glycoldibenzoate, dipropylene glycol dibenzoate, triethylene glycolcaprate-caprylate; monostearates such as, for example, glycerolmonostearate; citrate esters; organic acid esters; aromatic carboxylicesters; aliphatic dicarboxylic esters; fatty acid esters such as, forexample, stearic, oleic, myristic, palmitic, and sebacic acid esters;triacetin; poly(esters) such as, for example, phthalate polyesters,adipate polyesters, glutate polyesters, phthalates such as, for example,dialkyl phthalates, dimethyl phthalate, diethyl phthalate, isopropylphthalate, dibutyl phthalate, dihexyl phthalate, dioctyl phthalate,diisononyl phthalate, and diisodecyl phthalate; sebacates such as, forexample, alkyl sebacates, dimethyl sebacate, dibutyl sebacate;hydroxyl-esters such as, for example, lactate, alkyl lactates, ethyllactate, butyl lactate, allyl glycolate, ethyl glycolate, and glycerolmonostearate; citrates such as, for example, alkyl acetyl citrates,triethyl acetyl citrate, tributyl acetyl citrate, trihexyl acetylcitrate, alkyl citrates, triethyl citrate, and tributyl citrate; estersof castor oil such as, for example, methyl ricinolate; aromaticcarboxylic esters such as, for example, trimellitic esters, benzoicesters, and terephthalic esters; aliphatic dicarboxylic esters such as,for example, dialkyl adipates, alkyl allylether diester adipates,dibutoxyethoxyethyl adipate, diisobutyl adipate, sebacic esters, azelaicesters, citric esters, and tartaric esters; and fatty acid esters suchas, for example, glycerol, mono- di- or triacetate, and sodium diethylsulfosuccinate; and any analogs, derivatives, copolymers andcombinations thereof.

In other embodiments, the plasticizers include, but are not limited toethers and polyethers such as, for example, poly(alkylene glycols) suchas poly(ethylene glycols) (PEG), poly(propylene glycols), andpoly(ethylene/propylene glycols); low molecular weight poly(ethyleneglycols) such as, for example, PEG 400 and PEG 6000; PEG derivativessuch as, for example, methoxy poly(ethylene glycol) (mPEG); andester-ethers such as, for example, diethylene glycol dibenzoate,dipropylene glycol dibenzoate, and triethylene glycol caprate-caprylate;and any analogs, derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers include, but are not limited to,amides such as, for example, oleic amide, erucic amide, and palmiticamide; alkyl acetamides such as, for example, dimethyl acetamide anddimethyl formamide; sulfoxides such as for example, dimethyl sulfoxide;pyrrolidones such as, for example, n-methylpyrrolidone; sulfones suchas, for example, tetramethylene sulfone; acids such as, for example, oxamonoacids, oxa diacids such as 3,6,9-trioxaundecanedioic acid, polyoxadiacids, ethyl ester of acetylated citric acid, butyl ester ofacetylated citric acid, capryl ester of acetylated citric acid, anddiglycolic acids such as dimethylol propionic acid; and any analogs,derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers can be vegetable oils including,but not limited to, epoxidized soybean oil; linseed oil; castor oil;coconut oil; fractionated coconut oil; epoxidized tallates; and estersof fatty acids such as stearic, oleic, myristic, palmitic, and sebacicacid. In other embodiments, the plasticizers can be essential oilsincluding, but not limited to, angelica oil, anise oil, arnica oil,aurantii aetheroleum, valerian oil, basilici aetheroleum, bergamot oil,savory oil, bucco aetheroleum, camphor, cardamomi aetheroleum, cassiaoil, chenopodium oil, chrysanthemum oil, cinae aetheroleum, citronellaoil, lemon oil, citrus oil, costus oil, curcuma oil, carlina oil, elemioil, tarragon oil, eucalyptus oil, fennel oil, pine needle oil, pineoil, filicis, aetheroleum, galbanum oil, gaultheriae aetheroleum,geranium oil, guaiac wood oil, hazelwort oil, iris oil, hypericum oil,calamus oil, camomile oil, fir needle oil, garlic oil, coriander oil,carraway oil, lauri aetheroleum, lavender oil, lemon grass oil, lovageoil, bay oil, lupuli strobuli aetheroleum, mace oil, marjoram oil,mandarine oil, melissa oil, menthol, millefolii aetheroleum, mint oil,clary oil, nutmeg oil, spikenard oil, clove oil, neroli oil, niaouli,olibanum oil, ononidis aetheroleum, opopranax oil, orange oil, oreganooil, orthosiphon oil, patchouli oil, parsley oil, petit-grain oil,peppermint oil, tansy oil, rosewood oil, rose oil, rosemary oil, rueoil, sabinae aetheroleum, saffron oil, sage oil, sandalwood oil,sassafras oil, celery oil, mustard oil, serphylli aetheroleum,immortelle oil, fir oil, teatree oil, terpentine oil, thyme oil, juniperoil, frankincense oil, hyssop oil, cedar wood oil, cinnamon oil, andcypress oil; and other oils such as, for example, fish oil; and anyanalogs, derivatives, copolymers and combinations thereof.

The molecular weights of the plasticizers can vary. In some embodiments,the molecular weights of the plasticizers range from about 10 Daltons toabout 50,000 Daltons; from about 25 Daltons to about 25,000 Daltons;from about 50 Daltons to about 10,000 Daltons; from about 100 Daltons toabout 5,000 Daltons; from about 200 Daltons to about 2500 Daltons; fromabout 400 Daltons to about 1250 Daltons; and any range therein. In otherembodiments, the molecular weights of the plasticizers range from about400 Daltons to about 4000 Daltons; from about 300 Daltons to about 3000Daltons; from about 200 Daltons to about 2000 Daltons; from about 100Daltons to about 1000 Daltons; from about 50 Daltons to about 5000Daltons; and any range therein. The molecular weights are taught hereinas a number average molecular weight.

The amount of plasticizer used in the teachings herein, can range fromabout 0.001% to about 70%; from about 0.01% to about 60%; from about0.1% to about 50%; from about 0.1% to about 40%; from about 0.1% toabout 30%; from about 0.1% to about 25%; from about 0.1% to about 20%;from about 0.1% to about 10%; from about 0.4% to about 40%; from about0.6% to about 30%; from about 0.75% to about 25%; from about 1.0% toabout 20%; and any range therein, as a weight percentage based on thetotal weight of the polymer and agent or combination of agents.

It should be appreciated that any one or any combination of theplasticizers described above can be used in the teachings herein. Forexample, the plasticizers can be combined to obtain the desiredfunction. In some embodiments, a secondary plasticizer is combined witha primary plasticizer in an amount that ranges from about 0.001% toabout 20%; from about 0.01% to about 15%; from about 0.05% to about 10%;from about 0.75% to about 7.5%; from about 1.0% to about 5%, or anyrange therein, as a weight percentage based on the total weight of thepolymer any agent or combination of agents.

One embodiment applies gamma irradiation or electron beam (e-beam)sterilization. Other types of radio sterilization can be used.

In some embodiments, the drug-containing layer may be applied to asurface of a prosthesis, and the drug-reservoir layer may be applied onor over the drug layer. In some embodiments, the prosthesis can comprisea fitting for mechanically coupling to an adjacent tissue, such ascalcified or soft tissue, for example, a bone CBD or TCH or intra-organCBD or TCH. In some embodiments, the system may comprise an entirelyresorbable construct, such as a capsule, a tablet, a pellet, a shaft, arod, a sphere, disc, or a ring. In some embodiments, the resorbableconstruct may be configured for deployment in an anatomic environmentsuch as the gastrointestinal tract, a synovial joint, a cardiovascularlumen, a cardiovascular chamber, a urinary lumen, a urinary chamber, areproductive lumen, a reproductive chamber, a gynecological lumen, agynecological chamber, an endocrine lumen, or an endocrine chamber.

In one example, a tubular drain system can be CBD or TCHed, leading fromone of the ventricles of the brain to an abdominal position. One or moreportions, or all, or the drain system may be coated and configured topromote endothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs to preventexcessive fibrous cellular encapsulation and/or stenosis.

In another example, portions of a “venous” needle or “arterial” needlein an arteriovenous fistula may be coated and configured to promoteendothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs to preventstenosis and/or excessive cellular encapsulation. Many transcutaneousport or cannulation device configurations may be so treated.

In another example, portions of pacemaker, defibrillator, or other CBDor TCHable device leads, such as a distal portion configured to engage aportion of the endocardial wall, may be coated and configured to promoteendothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs to preventexcessive cellular encapsulation.

In another example, portions of an intraocular lens prosthesis, such asthe main body or legs of the prosthesis may be coated and configured topromote endothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs to preventexcessive cellular encapsulation.

In another example, portions of a bile duct or other duct, tube, vessel,or lumen prosthesis may be coated and configured to promoteendothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs to preventstenosis and/or excessive cellular encapsulation.

In another example, pellets or small prostheses used to treat tissuevolumes such as those of a prostate gland may be coated and configuredto promote endothelization/healing by substantially blocking elution ofantiproliferative drugs, before controllably eluting drugs.

In another example, immunosuppressants and/or cytotoxics, such as taxol,can be delivered in such devices to aid in the treatment of tumors, suchas prostate or other tumors. Pellets containing such drugs, for example,may be delivered through the urethra or by other surgical means.

An embodiment of the invention can be used where two or more segments ofbone need to be aligned and require flexibility and changes of materialproperties based on temperature when device is placed.

An embodiment of the invention can help with broken bones, trauma, orother types of surgery but also building design or transportationdesign.

All references, patents, patent applications or other documents citedare hereby incorporated by reference herein in their entirety.

A natural feel is achieved through viscoelastic harmony of propertiesbetween the existing tissue and the CBD or TCH. This can be done bymanipulating the viscous component of the CBD or TCH through flowproperties by way of the particle size and particle size distributionratios. The elastic component is intrinsic within the material tertiarystructure (molecular weight and steric hindrance) and cross linkingdensities. The interpenetrating polymer network hydrogels have a numberof desirable properties. These properties include high tensile strengthwith high water content, making the interpenetrating polymer networkhydrogels excellent for use in dermal filling applications. Otheradvantages and features include: longevity without touch up,hyper-volumic degradation, anatomic compliant and iso-osmoticcontrolled, among others.

The present invention has been described particularly in connection witha breast, butt, or body CBD or TCH, among others, but it will be obviousto those of skill in the art that the invention can have application toother parts of the body, such as the face, and generally to other softtissue or bone. Accordingly, the invention is applicable to replacingmissing or damaged soft tissue, structural tissue or bone, or forcosmetic tissue or bone replacement.

Although the present invention has been described in relation toparticular embodiments thereof, many other variations and modificationsand other uses will become apparent to those skilled in the art. It ispreferred, therefore, that the present invention be limited not by thespecific disclosure herein, but only by the appended claims. The othermethods, used for characterization of the products according to oneembodiment are described in the following examples which illustratepreferred embodiments of one embodiment without, however, being alimitation thereof. Variations and modifications can, of course, be madewithout departing from the spirit and scope of the invention.

What is claimed is:
 1. A method for treating burned human skin orwounded human skin on a human in need thereof consisting essentially ofadministering via a patch to the human skin in need thereoftherapeutically effective amounts of isolated cannabigerol, fibrinogen,collagen, and hyaluronic acid to effectively treat the human skin thathas been burned or wounded on the human in need thereof.
 2. The methodas claimed in claim 1, wherein the isolated cannabigerol is in an amountof 0.1 mg to 1000 mg.
 3. The method as claimed in claim 1, furtherconsisting essentially of isolated cannabidiol.
 4. The method as claimedin claim 1, further consisting essentially of isolated cannabichromene.5. The method as claimed in claim 1, wherein microneedles project fromthe patch.
 6. The method of claim 1, wherein the patch further consistsessentially of a compound selected from the group consisting of:dronabinol, ethanol, propylene glycol, dextran, heparin, acetaminophenwith codeine, acetaminophen with hydrocodone, acetaminophen,paracetamol, acetylsalicylic acid, ibuprofen, ketoprofen, naproxen,naproxen sodium, celecoxib, Sulindac, Oxaprozin, Salsalate, Piroxicam,Indomethacin, Etodolac, Meloxicam, Mabumetone, Keteroloc, KetorolacTromethamine, Tolmetin, Diclofenac, Diproqualone, Diflunisal, codeine,hydrocodone, oxycodone, fentanyl, propoxyphene, ticlopidine,chlopidogrel, enoxaparin, dalteparin, hirudin, bivalirudin, argatroban,danparoid, fluoroquinolone, paclitaxel, rapamycin, sirolimus,everolimus, biolimus, zotarolimus, tacrolimus, fibroblast growth factor,dexamethasone, angiopeptin, tranilast, transilast, halofuginon,acetylsalicylic acid, hirudin, ibuprofen, actinomycin D, tissue plasmaactivators, estradiol, transcription factor E2F1, poly(butylmethacrylate), poly(ethyl methacrylate), poly(hydroxylethylmethacrylate), poly(ethyl methacrylate-co-butyl methacrylate),copolymers of ethylene-methyl methacrylate,poly(2-acrylamido-2-methylpropane sulfonic acid), polymers andcopolymers of aminopropyl methacrylamide, poly(cyanoacrylates),poly(carboxylic acids), poly(vinyl alcohols), poly(maleic anhydride),copolymers of maleic anhydride, fluorinated polymers or copolymers suchas poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoropropene), poly(tetrafluoroethylene), poly(sulfone), poly(N-vinylpyrrolidone), poly(aminocarbonates), poly(iminocarbonates),poly(anhydride-co-imides), poly(hydroxyvalerate), poly(L-lactic acid),poly(L-lactide), poly(caprolactones), poly(lactide-co-glycolide),poly(hydroxybutyrates), poly(hydroxybutyrate-co-valerate),poly(dioxanones), poly(orthoesters), poly(anhydrides), poly(glycolicacid), poly(glycolide), poly(D,L-lactic acid), poly(D,L-lactide),poly(glycolic acid-co-trimethylene carbonate), poly(phosphoesters),poly(phosphoester urethane), poly(trimethylene carbonate),poly(iminocarbonate), poly(ethylene), poly(propylene)co-poly(ether-esters), poly(dioxanone) and poly(ethyleneoxide)/poly(lactic acid), poly(anhydrides), poly(alkylene oxalates),poly(phosphazenes), poly(urethanes), silicones, poly(esters),poly(olefins), copolymers of poly(isobutylene), copolymers ofethylene-alphaolefin, vinyl halide polymers and copolymers, poly(vinylchloride), poly(vinyl ethers), poly(vinyl methyl ether), poly(vinylidenehalides, poly(vinylidene chloride), poly(acrylonitrile), poly(vinylketones), poly(vinyl aromatics, poly(styrene), poly(vinyl esters),poly(vinyl acetate), copolymers of vinyl monomers and olefins,poly(ethylene-co-vinyl alcohol), copolymers of acrylonitrile-styrene,copolymers of ethylene-vinyl acetate, poly(carbonates),poly(oxymethylenes), poly(imides), poly(ester amides), poly(ethers),poly(alkylene glycols), poly(ethylene glycol), poly(propylene glycol),epoxy resins, polyurethanes, rayon, rayon-triacetate, fibrin, gelatin,chondroitin sulfate, dermatan sulfate (a copolymer of D-glucuronic acidor L-iduronic acid and N-acetyl-D-galactosamine), glycosaminoglycan,poly(N-acetylglucosamine), chitin, chitosan, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethylcellulose, an a-hydroxycarboxylic acid, a cyclic diester ofan a-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate,a cyclic oxalate, an epoxide, a glycol, a lactic acid, a glycolic acid,a lactide, a glycolide, an ethylene oxide, an ethylene glycol,polyesters, poly(ester amides), polyethylene glycol, polycaprolactones,poly(L-lactide), poly(D,L-lactide), poly(D,L-lactide-co-polyethyleneglycol) block copolymers, poly(D,L-lactide-co-trimethylene carbonate),polyglycolides, poly(lactide-co-glycolide), polydioxanones,polyorthoesters, polyanhydrides, poly(glycolic acid-co-trimethylenecarbonate), polyphosphoesters, polyphosphoester urethanes, poly(aminoacids), polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polycarbonates, polyurethanes, copoly(ether-esters),polyalkylene oxalates, and polyphosphazenes.